Researcher Profile and Settings

Master

Affiliation (Master)

• Faculty of Medicine　Internal Medicine　Internal Medicine

Affiliation (Master)

• Faculty of Medicine　Internal Medicine　Internal Medicine

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Profile and Settings

Degree

• M.D.（Ph.D.）

Profile and Settings

• Name (Japanese)

  Hashimoto

• Name (Kana)

  Daigo

• Name

  201301039153653334

Alternate Names

http://kaken.nii.ac.jp/d/r/20419576.ja.html

Achievement

Research Interests

• Innate Immunity   Macrophage   Graft versus host disease   Hematopoietic stem cell transplantation   

Research Areas

• Life sciences / Immunology
• Life sciences / Hematology and oncology

Research Experience

• 2018/04 - Today Hokkaido University Faculty of Medicine Department of Hematology Associate Professor
• 2015/10 - 2018/03 Hokkaido University Hospital Department of Hematology Senior Assistant Professor
• 2013 - 2015 Hokkaido University Department of Hematology Tenure-Track Assistant Professor
• 2007 Kyushu University

Education

• 2001 - 2005  Okayama University Graduate School of Medicine and Dentistry Sciences
• 1991 - 1997  Okayama University Medical School

Committee Memberships

• 2019/03 - Today   Japanese Society for Transplantation and Cellular Therapy   Program
• 2018/10 - Today   The Japanese Society of Hematology   Program
• 2015 - Today   The Japan Society of Transfusion Medicine and Cell Therapy   councilor
• 2015 - Today   Japanese Society of Hematology   councilor
• 2020   Japanese Society of Hematology   Editorial Board of Academic Journal
• 2017 -2019   The Japan Society of Transfusion Medicine and Cell Therapy   Editorial Board of Academic Journal
• 2018   Japanese Society of Immunotherapy for Hematological Disorders   councilor

Awards

• 2020/11 Clarivate Analytics Highly Cited Researchers 2020
  
• 2019/11 Clarivate Analytics Highly Cited Researchers 2019
   Immunology 

  受賞者: Daigo Hashimoto
• 2018/11 Clarivate Analytics Highly Cited Researchers 2018
   Immunology 

  受賞者: Daigo Hashimoto
• 2017/11 Clarivate Analytics Highly Cited Researchers 2017
   Immunology 

  受賞者: Daigo Hashimoto
• 2016/11 Clarivate Analytics Highly Cited Researchers 2016
   Immunology 

  受賞者: Daigo Hashimoto

Published Papers

• GVHD targets organoid-forming bile duct stem cells via a TGF-β-dependent manner.

  Yuta Hasegawa, Daigo Hashimoto, Zixuan Zhang, Toru Miyajima, Yumika Saito, Wenyu Li, Ryo Kikuchi, Hajime Senjo, Tomoko Sekiguchi, Takahiro Tateno, Xuanzhong Chen, Emi Yokoyama, Shuichiro Takahashi, Hiroyuki Ohigashi, Takahide Ara, Eiko Hayase, Isao Yokota, Takanori Teshima

  Blood 2024/06/21 

  Graft-versus-host disease (GVHD) is a major life-threatening complication that occurs after allogeneic hematopoietic cell transplantation (HCT). While adult tissue stem cells have been identified as targets of GVHD in the skin and gut, their role in hepatic GVHD is yet to be clarified. In the current study, we explored the fate of bile duct stem cells (BDSCs), capable of generating liver organoids in vitro, during hepatic GVHD after allogeneic HCT. We observed a significant expansion of biliary epithelial cells (BECs) upon injury early after allogeneic HCT. Organoid-forming efficiency from the bile duct was also significantly increased early after allogeneic HCT. Subsequently, the organoid-forming efficiency from bile ducts was markedly decreased in association with the reduction of BECs and the elevation of plasma concentrations of bilirubin, suggesting that GVHD targets BDSCs and impairs the resilience of BECs. The growth of liver organoids in the presence of liver-infiltrating mononuclear cells from allogeneic recipients, but not from syngeneic recipients, significantly reduced in a TGF--dependent manner. Administration of SB-431542, an inhibitor of TGF-β signaling, from day 14 to day 28 protected organoid-forming BDSCs against GVHD and mitigated biliary dysfunction after allogeneic HCT, suggesting that BDSCs are a promising therapeutic target for hepatic GVHD.
• Acute onset of constrictive pericarditis due to acute myelomonocytic leukemia: A case and literature review.

  Naoki Kosaka, Takanori Uchiyama, Masahiro Onozawa, Jun Nagai, Jiro Koya, Suguru Ishizaka, Toshiyuki Nagai, Yohei Ikebe, Kenjiro Kato, Zen-Ichi Tanei, Jun Sakakibara-Konishi, Yuta Hasegawa, Hiroyuki Ohigashi, Hideki Goto, Daigo Hashimoto, Hideki Ujiie, Satoshi Hirano, Satoshi Konno, Toshihisa Anzai, Koji Taniguchi, Shinya Tanaka, Takanori Teshima

  Internal medicine (Tokyo, Japan) 2024/04/16 

  We herein present a fatal case of constrictive pericarditis (CP) due to acute myelomonocytic leukemia (AMML) in a patient who initially complained of an acute onset of chest pain two days after COVID-19 vaccination. An autopsy revealed pericardial infiltration of leukemic cells. CP is rarely associated with leukemia and only 14 cases have been reported in the literature. The etiology of CP in previous reports included leukemic infiltration, graft-versus-host disease, drug-induced, post-radiation, autoimmune, and otherwise unidentified. This case indicates that leukemic infiltration can cause CP and that clinicians should include leukemia in the differential diagnosis of CP.
• Intravenous Administration of Mesenchymal Stem Cell-Derived Exosome Alleviates Spinal Cord Injury by Regulating Neutrophil Extracellular Trap Formation through Exosomal miR-125a-3p.

  Yutaka Morishima, Masahito Kawabori, Kazuyoshi Yamazaki, Soichiro Takamiya, Sho Yamaguchi, Yo Nakahara, Hajime Senjo, Daigo Hashimoto, Sakiko Masuda, Yoichiro Fujioka, Yusuke Ohba, Yuki Mizuno, Yuji Kuge, Miki Fujimura

  International journal of molecular sciences 25 (4) 2024/02/18 

  Spinal cord injury (SCI) leads to devastating sequelae, demanding effective treatments. Recent advancements have unveiled the role of neutrophil extracellular traps (NETs) produced by infiltrated neutrophils in exacerbating secondary inflammation after SCI, making it a potential target for treatment intervention. Previous research has established that intravenous administration of stem cell-derived exosomes can mitigate injuries. While stem cell-derived exosomes have demonstrated the ability to modulate microglial reactions and enhance blood-brain barrier integrity, their impact on neutrophil deactivation, especially in the context of NETs, remains poorly understood. This study aims to investigate the effects of intravenous administration of MSC-derived exosomes, with a specific focus on NET formation, and to elucidate the associated molecular mechanisms. Exosomes were isolated from the cell supernatants of amnion-derived mesenchymal stem cells using the ultracentrifugation method. Spinal cord injuries were induced in Sprague-Dawley rats (9 weeks old) using a clip injury model, and 100 μg of exosomes in 1 mL of PBS or PBS alone were intravenously administered 24 h post-injury. Motor function was assessed serially for up to 28 days following the injury. On Day 3 and Day 28, spinal cord specimens were analyzed to evaluate the extent of injury and the formation of NETs. Flow cytometry was employed to examine the formation of circulating neutrophil NETs. Exogenous miRNA was electroporated into neutrophil to evaluate the effect of inflammatory NET formation. Finally, the biodistribution of exosomes was assessed using 64Cu-labeled exosomes in animal positron emission tomography (PET). Rats treated with exosomes exhibited a substantial improvement in motor function recovery and a reduction in injury size. Notably, there was a significant decrease in neutrophil infiltration and NET formation within the spinal cord, as well as a reduction in neutrophils forming NETs in the circulation. In vitro investigations indicated that exosomes accumulated in the vicinity of the nuclei of activated neutrophils, and neutrophils electroporated with the miR-125a-3p mimic exhibited a significantly diminished NET formation, while miR-125a-3p inhibitor reversed the effect. PET studies revealed that, although the majority of the transplanted exosomes were sequestered in the liver and spleen, a notably high quantity of exosomes was detected in the damaged spinal cord when compared to normal rats. MSC-derived exosomes play a pivotal role in alleviating spinal cord injury, in part through the deactivation of NET formation via miR-125a-3p.
• 再発難治性びまん性大細胞型B細胞リンパ腫に対するCAR-T細胞療法後にpseudo-progressionを認めた1例

  藤井 文彰, 千葉 雅尋, 橋田 里妙, 長谷川 祐太, 大東 寛幸, 安本 篤史, 後藤 秀樹, 山口 圭介, 小野澤 真弘, 橋本 大吾, 豊嶋 崇徳

  臨床血液 (一社)日本血液学会-東京事務局 64 (12) 1523 - 1524 0485-1439 2023/12
• Incidence and course of Epstein-Barr virus viremia after allogeneic hematopoietic stem cell transplant for adult-onset systemic chronic active Epstein-Barr virus disease.

  Preeti Prerna M Vaswani, Masahiro Onozawa, Yuta Hasegawa, Hiroyuki Ohigashi, Takahide Ara, Toshihiro Matsukawa, Atsushi Yasumoto, Souichi Shiratori, Hideki Goto, Masao Nakagawa, Kaoru Kahata, Tomoyuki Endo, Daigo Hashimoto, Takanori Teshima

  Bone marrow transplantation 2023/09/05
• Type 1 Cryoglobulinemic Vasculitis Due to Monoclonal Gammopathy of Undetermined Significance Successfully Treated by Bortezomib Plus Dexamethasone.

  Ryo Kikuchi, Masahiro Onozawa, Jun Nagai, Satomi Okada, Yuta Hasegawa, Hiroyuki Ohigashi, Shintaro Mitamura, Taku Maeda, Emi Takakuwa, Yuichiro Fujieda, Hideki Goto, Daigo Hashimoto, Yoshihiro Matsuno, Takanori Teshima

  Internal medicine (Tokyo, Japan) 2023/06/14 

  Cryoglobulins are immunoglobulins that precipitate in cold conditions. Type I cryoglobulinemic vasculitis is associated with hematological malignancies. We herein report a case of steroid-resistant type 1 cryoglobulinemic vasculitis associated with monoclonal gammopathy of undetermined significance (MGUS) in a 47-year-old woman. By immunofixation of cryoglobulin, we found that the main component of cryoglobulin was the M protein due to MGUS, so treatment of MGUS was needed. Bortezomib+dexamethasone therapy resulted in a rapid decrease in cryoglobulin and improvement in the symptoms of cryoglobulinemic vasculitis. In refractory type I cryoglobulinemic vasculitis, treatment of the underlying gammaglobulinopathy should be considered.
• Calcineurin inhibitor inhibits tolerance induction by suppressing terminal exhaustion of donor T cells after allo-HCT.

  Hajime Senjo, Shinpei Harada, Shimpei I Kubota, Yuki Tanaka, Takahiro Tateno, Zixuan Zhang, Satomi Okada, Xuanzhong Chen, Ryo Kikuchi, Naoki Miyashita, Masahiro Onozawa, Hideki Goto, Tomoyuki Endo, Yuta Hasegawa, Hiroyuki Ohigashi, Takahide Ara, Yoshinori Hasegawa, Masaaki Murakami, Takanori Teshima, Daigo Hashimoto

  Blood 2023/05/22 

  Calcineurin inhibitor-based graft-versus-host disease (GVHD) prophylaxis is standard in allogeneic hematopoietic stem cell transplantation (HCT) but fails to induce long-term tolerance without chronic GVHD in a considerable number of patients. In this study, we addressed this long-standing question in mouse models of HCT. After HCT, alloreactive donor T cells rapidly differentiated into PD-1+ TIGIT+ terminally exhausted T cells (terminal-Tex). GVHD prophylaxis with cyclosporine (CSP) suppressed donor T-cell expression of TOX, a master regulator to promote differentiation of transitory exhausted T cells (transitory-Tex), expressing both inhibitory receptors and effector molecules, into terminal-Tex, and inhibited tolerance induction. Adoptive transfer of transitory-Tex, but not terminal-Tex, into secondary recipients developed chronic GVHD. Transitory-Tex maintained alloreactivity and thus PD-1 blockade restored graft-versus-leukemia (GVL) activity of transitory-Tex, not terminal-Tex. In conclusion, CSP inhibits tolerance induction by suppressing the terminal exhaustion of donor T cells, while maintaining GVL effects to suppress leukemia relapse.
• Subclinical minute FLT3-ITD clone can be detected in clinically FLT3-ITD-negative acute myeloid leukaemia at diagnosis.

  Shota Yokoyama, Masahiro Onozawa, Shota Yoshida, Naoki Miyashita, Hiroyuki Kimura, Shogo Takahashi, Toshihiro Matsukawa, Hideki Goto, Shinichi Fujisawa, Kosuke Miki, Daisuke Hidaka, Junichi Hashiguchi, Kentaro Wakasa, Makoto Ibata, Yukari Takeda, Akio Shigematsu, Katsuya Fujimoto, Yutaka Tsutsumi, Akio Mori, Toshimichi Ishihara, Yasutaka Kakinoki, Takeshi Kondo, Daigo Hashimoto, Takanori Teshima

  British journal of haematology 201 (6) 1144 - 1152 2023/04/17 

  Recent advances in next-generation sequencing (NGS) have enabled the detection of subclinical minute FLT3-ITD. We selected 74 newly diagnosed, cytogenetically normal acute myeloid leukaemia (AML) samples in which FLT3-ITD was not detected by gel electrophoresis. We sequenced them using NGS and found minute FLT3-ITDs in 19 cases. We compared cases with clinically relevant FLT3-ITD (n = 37), cases with minute FLT3-ITD (n = 19) and cases without detectable FLT3-ITD (n = 55). Molecular characteristics (location and length) of minute FLT3-ITD were similar to those of clinically relevant FLT3-ITD. Survival of cases with minute FLT3-ITD was similar to that of cases without detectable FLT3-ITD, whereas the relapse rate within 1 year after onset was significantly higher in cases with minute FLT3-ITD. We followed 18 relapsed samples of cases with clinically FLT3-ITD-negative at diagnosis. Two of 3 cases with minute FLT3-ITD relapsed with progression to clinically relevant FLT3-ITD. Two of 15 cases in which FLT3-ITD was not detected by NGS relapsed with the emergence of minute FLT3-ITD, and one of them showed progression to clinically relevant FLT3-ITD at the second relapse. We revealed the clonal dynamics of subclinical minute FLT3-ITD in clinically FLT3-ITD-negative AML. Minute FLT3-ITD at the initial AML can expand to become a dominant clone at relapse.
• Subcutaneous Panniculitis-like T-cell Lymphoma Lacking Subcutaneous Tumor Mimicking Adult-onset Still's Disease.

  Maria Tada, Shion Kachi, Masahiro Onozawa, Yuichiro Fujieda, Shota Yoshida, Yotaro Oki, Kazuro Kamada, Jun Nagai, Satomi Okada, Ryo Kikuchi, Ryo Hisada, Yuta Hasegawa, Hiroyuki Ohigashi, Hideki Goto, Daigo Hashimoto, Shinichi Nakazato, Yoshihiro Matsuno, Takanori Teshima, Tatsuya Atsumi

  Internal medicine (Tokyo, Japan) 2023/03/15 

  We herein report a case of subcutaneous panniculitis-like T-cell lymphoma (SPTCL) resembling adult-onset Still's disease (AOSD). A 40-year-old woman presented with a fever, erythema, and painful subcutaneous nodules on the trunk. Laboratory data and a bone marrow analysis showed hemophagocytic syndrome. Although AOSD was suspected, based on a histopathological evaluation of the erythema, she was diagnosed with SPTCL. She was refractory to combination chemotherapy but achieved durable remission with cyclosporine monotherapy. Genetic testing revealed a homozygous HAVCR2 c.245A>G variant (rs184868814) that had caused NLRP3 inflammasome activation. SPTCL and AOSD share a pathogenesis in terms of NLRP3 inflammasome activation, so the clinical phenotype of SPTCL reasonably mimics AOSD.
• Decreased Paneth cell α-defensins promote fibrosis in a choline-deficient L-amino acid-defined high-fat diet-induced mouse model of nonalcoholic steatohepatitis via disrupting intestinal microbiota

  Shunta Nakamura, Kiminori Nakamura, Yuki Yokoi, Yu Shimizu, Shuya Ohira, Mizu Hagiwara, Zihao Song, Li Gan, Tomoyasu Aizawa, Daigo Hashimoto, Takanori Teshima, Andre J. Ouellette, Tokiyoshi Ayabe

  Scientific Reports 13 (1) 2023/03/09 

  Abstract Nonalcoholic steatohepatitis (NASH) is a chronic liver disease characterized by fibrosis that develops from fatty liver. Disruption of intestinal microbiota homeostasis, dysbiosis, is associated with fibrosis development in NASH. An antimicrobial peptide α-defensin secreted by Paneth cells in the small intestine is known to regulate composition of the intestinal microbiota. However, involvement of α-defensin in NASH remains unknown. Here, we show that in diet-induced NASH model mice, decrease of fecal α-defensin along with dysbiosis occurs before NASH onset. When α-defensin levels in the intestinal lumen are restored by intravenous administration of R-Spondin1 to induce Paneth cell regeneration or by oral administration of α-defensins, liver fibrosis is ameliorated with dissolving dysbiosis. Furthermore, R-Spondin1 and α-defensin improved liver pathologies together with different features in the intestinal microbiota. These results indicate that decreased α-defensin secretion induces liver fibrosis through dysbiosis, further suggesting Paneth cell α-defensin as a potential therapeutic target for NASH.
• Conditioning Regimens are Associated with Distinct Patterns of Microbiota Injury in Allogeneic Hematopoietic Cell Transplantation.

  Roni Shouval, Nicholas R Waters, Antonio L C Gomes, Corrado Zuanelli Brambilla, Teng Fei, Sean M Devlin, Chi L Nguyen, Kate A Markey, Anqi Dai, John B Slingerland, Annelie G Clurman, Emily Fontana, Luigi A Amoretti, Roberta J Wright, Tobias M Hohl, Ying Taur, Anthony D Sung, Daniela Weber, Daigo Hashimoto, Takanori Teshima, Nelson J Chao, Ernst Holler, Michael Scordo, Sergio A Giralt, Miguel-Angel Perales, Jonathan U Peled, Marcel R M van den Brink

  Clinical cancer research : an official journal of the American Association for Cancer Research 29 (1) 165 - 173 2023/01/04 

  PURPOSE: The gut microbiota is subject to multiple insults in allogeneic hematopoietic cell transplantation (allo-HCT) recipients. We hypothesized that preparative conditioning regimens contribute to microbiota perturbation in allo-HCT. EXPERIMENTAL DESIGN: This was a retrospective study that evaluated the relationship between conditioning regimens exposure in 1,188 allo-HCT recipients and the gut microbiome. Stool samples collected from 20 days before transplantation up to 30 days after were profiled using 16S rRNA sequencing. Microbiota injury was quantified by changes in α-diversity. RESULTS: We identified distinct patterns of microbiota injury that varied by conditioning regimen. Diversity loss was graded into three levels of conditioning-associated microbiota injury (CMBI) in a multivariable model that included antibiotic exposures. High-intensity regimens, such as total body irradiation (TBI)-thiotepa-cyclophosphamide, were associated with the greatest injury (CMBI III). In contrast, the nonmyeloablative regimen fludarabine-cyclophosphamide with low-dose TBI (Flu/Cy/TBI200) had a low-grade injury (CMBI I). The risk of acute GVHD correlated with CMBI degree. Pretransplant microbial compositions were best preserved with Flu/Cy/TBI200, whereas other regimens were associated with loss of commensal bacteria and expansion of Enterococcus. CONCLUSIONS: Our findings support an interaction between conditioning at the regimen level and the extent of microbiota injury.
• Reactive granulopoiesis depends on T-cell production of IL-17A and neutropenia-associated alteration of gut microbiota.

  Xuanzhong Chen, Daigo Hashimoto, Ko Ebata, Shuichiro Takahashi, Yu Shimizu, Ryuga Shinozaki, Yuta Hasegawa, Ryo Kikuchi, Hajime Senjo, Kazuki Yoneda, Zixuan Zhang, Shinpei Harada, Eiko Hayase, Takahide Ara, Hiroyuki Ohigashi, Yoichiro Iwakura, Kiminori Nakamura, Tokiyoshi Ayabe, Takanori Teshima

  Proceedings of the National Academy of Sciences of the United States of America 119 (48) e2211230119  2022/11/29 

  Granulopoiesis in the bone marrow adjusts cellular output as demand for neutrophils changes. Reactive granulopoiesis is induced by profound neutropenia, but its mechanism remains to be clarified. We herein explored its mechanisms using mouse models of syngeneic hematopoietic stem cell transplantation (SCT) and 5-fluorouracil-induced neutropenia. After SCT, T cell production of IL-17A was up-regulated. Neutrophil recovery was significantly delayed in IL-17A-deficient or T cell-deficient RAG1-/- mice, and adoptive transfer of wild-type (WT) T cells facilitated neutrophil engraftment. Gut decontamination with oral antibiotics suppressed T cell production of IL-17A and impaired neutrophil recovery. Transplantation of fecal microbiota collected from neutropenic, not naive, mice promoted neutrophil recovery in these mice, suggesting that neutropenia-associated microbiota had a potential to stimulate reactive granulopoiesis. Our study uncovered a cross talk between gut microbiota and neutropenia after SCT and chemotherapy.
• Unilateral recurrent laryngeal nerve palsy detected by PET/CT in a patient with mediastinal T-cell lymphoblastic lymphoma.

  Toru Miyajima, Yuta Hasegawa, Daigo Hashimoto, Takanori Teshima

  International journal of hematology 116 (1) 3 - 4 2022/07
• High CRP-albumin ratio predicts poor prognosis in transplant ineligible elderly patients with newly diagnosed acute myeloid leukemia.

  Hajime Senjo, Masahiro Onozawa, Daisuke Hidaka, Shota Yokoyama, Satoshi Yamamoto, Yutaka Tsutsumi, Yoshihito Haseyama, Takahiro Nagashima, Akio Mori, Shuichi Ota, Hajime Sakai, Toshimichi Ishihara, Takuto Miyagishima, Yasutaka Kakinoki, Mitsutoshi Kurosawa, Hajime Kobayashi, Hiroshi Iwasaki, Daigo Hashimoto, Takeshi Kondo, Takanori Teshima

  Scientific reports 12 (1) 8885 - 8885 2022/05/25 

  Acute myeloid leukemia (AML) patients older than 65 years have a poor prognosis. Recently, CAR (C-reactive-protein/albumin ratio) has been actively reported as a prognostic index reflecting the nutritional and inflammatory status of elderly patients with solid tumors, but the usefulness of this index as a prognostic indicator in transplant-ineligible elderly AML patients has not been investigated. We studied genetic alterations and CARs in 188 newly diagnosed AML patients aged 65 years or older who were treated in a multicenter setting and had treated without HSCT. Both NCCN 2017 risk group, reflecting the genetic component of the tumor, and CAR, reflecting the inflammatory and nutritional status of the patient, successfully stratified the overall survival (OS) of the patients (2-year OS; CAR low vs high, 42.3% vs 17.8%, P < 0.001). Furthermore, in multivariate analysis, NCCN 2017 poor group and high CAR were extracted as independent poor prognostic factors predicting 2-year OS in the current study. We found, for the first time, that CAR at diagnosis predicted the prognosis of elderly patients with newly diagnosed AML treated without HSCT.
• Gilteritinib enhances graft-versus-leukemia effects against FLT3-ITD mutant leukemia after allogeneic hematopoietic stem cell transplantation.

  Zixuan Zhang, Yuta Hasegawa, Daigo Hashimoto, Hajime Senjo, Ryo Kikuchi, Xuanzhong Chen, Kazuki Yoneda, Tomoko Sekiguchi, Tatsuya Kawase, Hirofumi Tsuzuki, Takashi Ishio, Takahide Ara, Hiroyuki Ohigashi, Masao Nakagawa, Takanori Teshima

  Bone marrow transplantation 57 (5) 775 - 780 2022/05 

  Allogeneic hematopoietic stem cell transplantation (allo-SCT) is a potentially curative therapy for FLT3 internal tandem duplication mutant (FLT3-ITD+) acute myeloid leukemia, but relapse rate is high. A recent study showed that sorafenib, a first generation FLT3 and multikinase inhibitor, enhanced graft-versus-leukemia (GVL) effects against FLT3-ITD+ leukemia via interleukin-15 (IL-15) production. However, it remains to be clarified whether this effect could be mediated by selective FLT3 inhibition. We investigated whether gilteritinib, a selective FLT3 inhibitor, could enhance GVL effects against FLT3-ITD transfected Ba/F3 leukemia (Ba/F3-FLT3-ITD) in mice. Oral administration of gilteritinib from day +5 to +14 after allo-SCT reduced expression of the co-inhibitory receptors PD-1 and TIGIT on donor CD8+ T cells and enhanced IL-15 expression in Ba/F3-FLT3-ITD. Bioluminescent imaging using luciferase-transfected Ba/F3-FLT3-ITD demonstrated that gilteritinib significantly suppressed leukemia expansion after allo-SCT, whereas it did not impact the morbidity or mortality of graft-versus-host disease (GVHD), resulting in significant improvement of overall survival. In conclusion, short-term administration of gilteritinib after allo-SCT enhanced GVL effects against FLT3-ITD+ leukemia without exacerbating GVHD.
• HIV関連悪性リンパ腫の臨床的特徴

  遠藤 知之, 後藤 秀樹, 荒 隆英, 長谷川 祐太, 横山 翔大, 高橋 承吾, 米田 和樹, 橋本 大吾, 橋野 聡, 豊嶋 崇徳

  日本エイズ学会誌 (一社)日本エイズ学会 24 (1) 13 - 20 1344-9478 2022/02 

  背景:HIV関連悪性リンパ腫は、死亡率の高い予後不良な合併症である。HIV感染者では、背景に免疫不全が存在するため、その臨床的特徴はHIV非感染者に発生する悪性リンパ腫とは異なっていることが指摘されており、至適治療法に関しても定まったものがない。方法:2006年4月から2020年3月までに当院において悪性リンパ腫の診断・治療を行ったHIV感染症患者を対象とし、患者基本情報、悪性リンパ腫の診断・臨床経過等を診療録から収集し後方視的に解析した。また、同時期に当院で初発時治療を行ったHIV非感染悪性リンパ腫359例と比較した。結果:対象症例は12例で全例男性であった。リンパ腫発症時の年齢中央値は47.5歳(33～64歳)、末梢血CD4陽性リンパ球数の中央値は54/μL(3～267/μL)であった。組織型はdiffuse large B-cell lymphoma 8例、Burkitt lymphoma 2例、Hodgkin lymphoma 1例、T-cell lymphoma 1例であった。また、HIV非感染者と比較してEBER陽性例が有意に多く、Ki-67高値例も多い傾向があった。さらに、治療時の血球減少が高度で、全例でgrade 4の好中球減少があり、治療中の感染症も有意に多く認められた。5年全生存率は83.3%であり、HIV非感染悪性リンパ腫症例の5年全生存率84.0%と同等であった。考察:HIV関連悪性リンパ腫は、病理組織のみでは診断が困難なことがあるため、表面形質や遺伝子検査などの情報も含めて総合的に判断する必要がある。HIV感染者ではHIV非感染者と比べて治療時の血球減少が高度であったが、治療を完遂できればHIV非感染者と同等の生命予後が得られる可能性があるため、治療開始早期の感染症対策が重要と考えられた。(著者抄録)
• [Bing-Neel syndrome successfully treated with tirabrutinib].

  Keito Yokoyama, Hiroyuki Ohigashi, Toru Miyajima, Naoki Miyashita, Satomi Okada, Yuta Hasegawa, Junichi Sugita, Masahiro Onozawa, Daigo Hashimoto, Takanori Teshima

  [Rinsho ketsueki] The Japanese journal of clinical hematology 63 (8) 870 - 875 2022 

  Bing-Neel syndrome (BNS) is a rare disease manifestation of Waldenström's macroglobulinemia characterized by abnormal lymphoplasmacytoid cells infiltration of the central nervous system. In September 2019, a 46-year-old man presented to a previous hospital with hand tremors, nausea, and dysuria. Demyelination of cerebral white matter and the spinal cord was discovered using MRI. Steroid pulse therapy was used to treat inflammatory demyelinating disease, and it provided temporary relief, but the symptoms returned when the steroids were stopped. He was referred to our hospital in June 2020, for further evaluation with the possibility of hematological malignancy. BNS was diagnosed based on the presence of abnormal lymphoplasmacytoid cells in the bone marrow and cerebrospinal fluid (CSF), as well as the presence of the MYD88L265P mutation in the CSF specimen. In July 2020, BR (bendamustine, rituximab) therapy was administered, but it was ineffective. Oral administration of tirabrutinib, which was recently approved for WM, began in August 2020. He has achieved long-term remission and steroid withdrawal, with no notable side effects. This is the second report of successful treatment of BNS with tirabrutinib. More research is needed to confirm tirabrutinib's efficacy in the treatment of BNS.
• Intravenous transplantation of amnion-derived mesenchymal stem cells promotes functional recovery and alleviates intestinal dysfunction after spinal cord injury.

  Soichiro Takamiya, Masahito Kawabori, Kazuyoshi Yamazaki, Sho Yamaguchi, Aki Tanimori, Koji Yamamoto, Shunsuke Ohnishi, Toshitaka Seki, Kotaro Konno, Khin Khin Tha, Daigo Hashimoto, Masahiko Watanabe, Kiyohiro Houkin, Miki Fujimura

  PloS one 17 (7) e0270606  2022 

  Spinal cord injury (SCI) is often accompanied by gastrointestinal dysfunction due to the disconnection of the spinal autonomic nervous system. Gastrointestinal dysfunction reportedly upregulates intestinal permeability, leading to bacterial translocation of the gut microbiome to the systemic circulation, which further activates systemic inflammation, exacerbating neuronal damage. Mesenchymal stem cells (MSC) reportedly ameliorate SCI. Here, we aimed to investigate their effect on the associated gastrointestinal dysfunction. Human amnion-derived MSC (AMSCs) were intravenously transplanted one day after a rat model of midthoracic SCI. Biodistribution of transplanted cells, behavioral assessment, and histological evaluations of the spinal cord and intestine were conducted to elucidate the therapeutic effect of AMSCs. Bacterial translocation of the gut microbiome was examined by in situ hybridization and bacterial culture of the liver. Systemic inflammations were examined by blood cytokines, infiltrating immune cells in the spinal cord, and the size of the peripheral immune tissue. AMSCs released various neurotrophic factors and were mainly distributed in the liver and lung after transplantation. AMSC-transplanted animals showed smaller spinal damage and better neurological recovery with preserved neuronal tract. AMSCs transplantation ameliorated intestinal dysfunction both morphologically and functionally, which prevented translocation of the gut microbiome to the systemic circulation. Systemic inflammations were decreased in animals receiving AMSCs in the chronic phase. Intravenous AMSC administration during the acute phase of SCI rescues both spinal damage and intestinal dysfunction. Reducing bacterial translocation may contribute to decreasing systemic inflammation.
• Aleukemic Extramedullary Blast Crisis as an initial presentation of Chronic Myeloid Leukemia with E1A3 BCR-ABL1 Fusion Transcript

  Naoki Miyashita, Masahiro Onozawa, Keito Suto, Shinichi Fujisawa, Nanase Okazaki, Daisuke Hidaka, Hiroyuki Ohigashi, Atsushi Yasumoto, Junichi Sugita, Daigo Hashimoto, Yoshihiro Matsuno, Takanori Teshima

  Internal Medicine 61 (7) 1049 - 1054 0918-2918 2022 [Refereed]
   

  Right neck swelling and pain occurred in a 49-year-old man. A Blood count showed a slight increase in platelet count without leukemoid reaction. After a biopsy of the cervical mass and bone marrow aspiration, a diagnosis of extramedullary blast crisis (EBC) of chronic myeloid leukemia (CML) was made. FISH analysis showed a BCR-ABL1 fusion signal, but results of RT-PCR for major and minor BCR-ABL1 transcripts were negative. We identified a rare e1a3 BCR-ABL1 fusion transcript. Administration of dasatinib resulted in disappearance of the extramedullary tumor. This is the first reported case of CML-EBC with e1a3 transcript. An aleukemic extramedullary tumor can be the initial presentation of CML.
• Low-dose antithymocyte globulin inhibits chronic graft-versus-host disease in peripheral blood stem cell transplantation from unrelated donors

  Souichi Shiratori, Junichi Sugita, Shigeo Fuji, Jun Aoki, Masashi Sawa, Yukiyasu Ozawa, Daigo Hashimoto, Ken-ichi Matsuoka, Kazunori Imada, Noriko Doki, Takashi Ashida, Yasunori Ueda, Masatsugu Tanaka, Yasushi Sawayama, Tatsuo Ichinohe, Seitaro Terakura, Satoko Morishima, Yoshiko Atsuta, Takahiro Fukuda, Takanori Teshima

  Bone Marrow Transplantation 56 (9) 2231 - 2240 0268-3369 2021/09 [Refereed]
   

  Antithymocyte globulin (ATG) has been shown to reduce chronic graft-versus-host disease (GVHD) particularly in allogeneic peripheral blood stem cell transplantation (PBSCT) from unrelated donors; however, anti-GVHD effects of lower doses of ATG remains to be elucidated. We conducted a nationwide retrospective study to compare the outcomes of unrelated PBSCT with or without rabbit ATG (thymoglobulin) in 287 patients. A median ATG dose was 2.0 mg/kg. The primary endpoint, the cumulative incidence of moderate-severe chronic GVHD at 2 years was 22.1% in the ATG group, which was significantly less than that in the non-ATG group (36.3%, P = 0.025). The ATG group had a higher incidence of immunosuppressant discontinuation, GVHD-free, relapse-free survival, and moderate-severe chronic GVHD-free, relapse-free survival at 2 years compared to the non-ATG group. The incidences of grade III-IV aGVHD and moderate-severe chronic GVHD were significantly higher in patients with high absolute lymphocyte count (ALC) before the administration of ATG, whereas relapse rate was significantly higher in patients with low ALC before ATG. In conclusion, low-dose ATG effectively suppresses chronic GVHD in unrelated PBSCT, and ALC before ATG may be a potential predictor for GVHD and relapse.
• Novel Insights Into the Mechanism of GVHD-Induced Tissue Damage

  Takahide Ara, Daigo Hashimoto

  Frontiers in Immunology 12 2021/08/27 [Refereed][Invited]
   

  Prophylaxis for and treatment of graft-versus-host disease (GVHD) are essential for successful allogeneic hematopoietic stem cell transplantation (allo-SCT) and mainly consist of immunosuppressants such as calcineurin inhibitors. However, profound immunosuppression can lead to tumor relapse and infectious complications, which emphasizes the necessity of developing novel management strategies for GVHD. Emerging evidence has revealed that tissue-specific mechanisms maintaining tissue homeostasis and promoting tissue tolerance to combat GVHD are damaged after allo-SCT, resulting in exacerbation and treatment refractoriness of GVHD. In the gastrointestinal tract, epithelial regeneration derived from intestinal stem cells (ISCs), a microenvironment that maintains healthy gut microbiota, and physical and chemical mucosal barrier functions against pathogens are damaged by conditioning regimens and/or GVHD. The administration of growth factors for cells that maintain intestinal homeostasis, such as interleukin-22 (IL-22) for ISCs, R-spondin 1 (R-Spo1) for ISCs and Paneth cells, and interleukin-25 (IL-25) for goblet cells, mitigates murine GVHD. In this review, we summarize recent advances in the understanding of GVHD-induced tissue damage and emerging strategies for the management of GVHD.
• GVHD prophylaxis with dipeptidyl peptidase 4 inhibition

  Daigo Hashimoto

  血液内科 83 (2) 270 - 274 2021/08 [Not refereed][Invited]
  
• XIAP欠損症に対して非血縁者間骨髄移植を施行して移植後赤芽球癆を認めた1例

  千葉 雅尋, 杉田 純一, 宮下 直樹, 須藤 啓斗, 日高 大輔, 大東 寛幸, 安本 篤史, 小野澤 真弘, 橋本 大吾, 豊嶋 崇徳

  臨床血液 (一社)日本血液学会-東京事務局 62 (7) 848 - 849 0485-1439 2021/07
• 髄外腫瘤で発症したe1a3 BCR-ABL陽性慢性骨髄性白血病

  宮下 直樹, 小野澤 真弘, 須藤 啓斗, 日高 大輔, 大東 寛幸, 安本 篤史, 杉田 純一, 橋本 大吾, 豊嶋 崇徳

  臨床血液 (一社)日本血液学会-東京事務局 62 (7) 849 - 849 0485-1439 2021/07
• High lymphocyte counts before antithymocyte globulin administration predict acute graft-versus-host disease

  Souichi Shiratori, Hiroyuki Ohigashi, Takahide Ara, Atsushi Yasumoto, Hideki Goto, Masao Nakagawa, Junichi Sugita, Masahiro Onozawa, Kaoru Kahata, Tomoyuki Endo, Daigo Hashimoto, Takanori Teshima

  Annals of Hematology 100 (5) 1321 - 1328 0939-5555 2021/05 [Refereed]
   

  Antithymocyte globulin (ATG) reduces severe acute and chronic graft-versus-host disease (GVHD) in allogeneic peripheral blood stem cell transplantation (PBSCT). However, risk factors for severe acute GVHD in PBSCT using ATG remain to be determined. We conducted a single-center, retrospective study to analyze the association of acute GVHD requiring systemic corticosteroid (SC-aGVHD) with absolute lymphocyte counts (ALC) before the administration of ATG or conditioning in 53 patients with HLA-matched PBSCT using low-dose thymoglobulin (2 mg/kg) after myeloablative conditioning. The cumulative incidence of SC-aGVHD was 17.0% and ALC before ATG were significantly higher in patients with SC-aGVHD compared to that in patients without it (median, 0.15 × 109/L vs 0.06 × 109/L, P = 0.047). The cumulative incidence of SC-aGVHD was significantly higher in patients with high ALC before ATG (≥ 0.15 × 109/L) than in those with low ALC (38.5% vs 10.0%, P = 0.016). Non-relapse mortality (NRM) was also significantly higher in the high ALC before ATG group than the low ALC before ATG group (2-year NRM: 23.9% vs 6.0%, P = 0.048), leading to worse survival (2-year overall survival: 69.2% vs 83.5%, P = 0.039). Our study suggested that high ALC before ATG is a risk factor for SC-aGVHD.
• Extramedullary hematopoiesis of the cranial dura

  Keito Suto, Junichi Sugita, Daigo Hashimoto, Hiroyuki Kameda, Tomoko Mitsuhashi, Takanori Teshima

  International Journal of Hematology 113 (3) 315 - 317 0925-5710 2021/03 [Refereed]
  
• Acute GVHD

  Daigo Hashimoto

  炎症と免疫 29 (2) 137 - 142 2021/02 [Not refereed][Invited]
  
• [Emergence of mutation in the colony-stimulating factor 3 receptor gene during follow-up of unclassifiable myeloproliferative neoplasm].

  Shinpei Harada, Kohei Okada, Shota Yokoyama, Daisuke Hidaka, Eiko Hayase, Masahiro Onozawa, Hideki Goto, Daigo Hashimoto, Kaoru Kahata, Tomoyuki Endo, Takanori Teshima

  [Rinsho ketsueki] The Japanese journal of clinical hematology 62 (11) 1609 - 1614 2021 

  A 25-year-old male with a medical history of stress polycythemia was admitted to a previous hospital for leukocytosis, anemia, and thrombocytopenia. Bone marrow examination revealed left-shifted myeloid hyperplasia without increased blasts and normal male karyotype. No mutations of JAK2, V617F, and colony-stimulating factor 3 receptor gene (CSF3R) were detected. Fluorescence in-situ hybridization for BCR-ABL1 and FIP1L1-PDGFRA were negative. Based on these findings, a diagnosis of an unclassifiable myeloproliferative neoplasm was made, and he was started on hydroxyurea treatment. He was referred to our hospital in April 2016 for transfusion dependence. Bone marrow examination performed at our hospital revealed granulocytic dysplasia and CSF3R T618I was detected. After induction therapy, CSF3R T618I became undetectable, and he went on to undergo allogeneic stem cell transplantation in October 2016. He has been in remission for >4 years posttransplantation. CSF3R T618I is one of the genes responsible for chronic neutrophilic leukemia and atypical chronic myeloid leukemia, suggesting its involvement in the pathogenesis of this case.
• 急性前骨髄球性白血病に対する同種造血幹細胞移植27年後に発症したドナー細胞由来未分化大細胞リンパ腫の1例

  菊池 遼, 小野澤 真弘, 今本 鉄平, 高橋 秀一郎, 杉田 純一, 橋本 大吾, 橋野 聡, 松野 吉宏, 豊嶋 崇徳

  日本内科学会雑誌 (一社)日本内科学会 110 (1) 92 - 98 0021-5384 2021/01 

  54歳男性。右鼠径リンパ節腫脹を主訴とした。27歳時に急性前骨髄球性白血病に対しHLA適合の兄から骨髄移植を受けていた。53歳時に右大腿外側部にケロイド様皮疹が出現し、皮膚生検の診断はanaplastic lymphoma kinase(ALK)陰性の未分化大細胞リンパ腫(ALCL)であった。電子線治療で皮膚病変は消失したが、7ヵ月後にFDG-PETで全身のリンパ節病変(鎖骨上窩、傍大動脈、右鼠径部)を認めた。再発病変を疑い、右鼠径リンパ節を生検したところ、右大腿皮膚生検同様の組織所見を認め、ALK陰性ALCLと診断した。末梢血をドナー細胞、頬粘膜をレシピエント細胞としてキメリズム解析を行い、ドナー由来のALCLと診断した。ALCLに対しCHOP療法(cyclophosphamide、doxorubicin、vincristine、prednisolone)を行ったが、病変の増大を認め、brentuximab vedotin(BV)単剤による治療に変更した。経過は良好で、現在まで完全奏効を維持している。
• A novel nutritional index “simplified CONUT” and the disease risk index independently stratify prognosis of elderly patients with acute myeloid leukemia

  Hajime Senjo, Masahiro Onozawa, Daisuke Hidaka, Shota Yokoyama, Satoshi Yamamoto, Yutaka Tsutsumi, Yoshihito Haseyama, Takahiro Nagashima, Akio Mori, Shuichi Ota, Hajime Sakai, Toshimichi Ishihara, Takuto Miyagishima, Yasutaka Kakinoki, Mitsutoshi Kurosawa, Hajime Kobayashi, Hiroshi Iwasaki, Daigo Hashimoto, Takeshi Kondo, Takanori Teshima

  Scientific Reports 10 (1) 19400 - 19400 2020/12 [Refereed]
   

  Elderly patients aged 65 or older with acute myeloid leukemia (AML) have poor prognosis. The risk stratification based on genetic alteration has been proposed in national comprehensive cancer network (NCCN) guideline but its efficacy was not well verified especially in real world elderly patients. The nutritional status assessment using controlling nutritional status (CONUT) score is a prognostic biomarker in elderly patients with solid tumors but was not examined in elderly AML patients. We performed prospective analysis of genetic alterations of 174 patients aged 65 or older with newly diagnosed AML treated without hematopoietic stem cell transplantation (HSCT) and developed simplified CONUT (sCONUT) score by eliminating total lymphocyte count from the items to adapt AML patients. In this cohort, both the NCCN 2017 risk group and sCONUT score successfully stratified the overall survival (OS) of the elderly patients. A multivariable analysis demonstrated that adverse group in NCCN 2017 and high sCONUT score were independently associated with poor 2-year OS. Both risk stratification based on NCCN 2017 and sCONUT score predict prognosis in the elderly patients with newly diagnosed AML.
• The role of intestinal dysbiosis in allogeneic stem cell transplantation

  Daigo Hashimoto

  血液内科 81 (5) 707 - 712 2020/11 [Not refereed][Invited]
  
• Validation and comparison of prognostic values of GNRI, PNI, and CONUT in newly diagnosed diffuse large B cell lymphoma.

  Toshihiro Matsukawa, Keito Suto, Minoru Kanaya, Koh Izumiyama, Koichiro Minauchi, Shota Yoshida, Hisashi Oda, Takuto Miyagishima, Akio Mori, Shuichi Ota, Daigo Hashimoto, Takanori Teshima

  Annals of hematology 99 (12) 2859 - 2868 2020/09/24 [Refereed][Not invited]
   

  Diffuse large B cell lymphoma (DLBCL) is the most common type of aggressive non-Hodgkin lymphoma. Emerging evidence indicates that poor nutritional status determined with nutritional indices such as geriatric nutritional risk index (GNRI), prognostic nutritional index (PNI), and controlling nutritional status score (CONUT) was associated with poor prognosis of DLBCL. We conducted this multicenter retrospective study to validate and compare prognostic values of the three indices in 615 newly diagnosed DLBCL patients. The overall survival (OS) in patients with poor nutritional status determined with each of these nutritional indices were significantly inferior compared with that in those without nutritional risks (5-year OS in patients with GNRI < 95.7 and GNRI ≥ 95.7 were 56.4% and 83.5%, P < 0.001; PNI < 42.4 and PNI ≥ 42.4 were 56.1% and 81.0%, P < 0.001; CONUT > 4 and CONUT ≤ 4 were 53.1% and 77.1%, P < 0.001). GNRI and CONUT were independent prognostic predictors for OS (GNRI < 95.7, hazard ratio [HR] 1.83, 95% confidence interval [CI] 1.22-2.74, P = 0.0032; CONUT > 4, HR 1.53, 95% CI 1.05-2.23, P = 0.028) after multivariate analyses. Nutritional status determined with GNRI affected OS more strongly in the patients with nongerminal center B cell-like (nonGCB) DLBCL compared with that in those with GCB-type DLBCL. In conclusion, baseline poor nutritional status determined based on GNRI or CONUT was an independent risk factor of newly diagnosed DLBCL, and GNRI was also useful as an independent prognostic factor for patients with nonGCB-type DLBCL.
• Feasibility and efficacy of low-dose pegfilgrastim for CD34+ cell mobilization in lymphoma.

  Hideki Goto, Daisuke Hidaka, Satoshi Yamamoto, Koji Hayasaka, Rie Michimata, Ikuko Kagawa, Kana Sunagoya, Hiroaki Iijima, Eiko Hayase, Souichi Shiratori, Kohei Okada, Junichi Sugita, Masahiro Onozawa, Daigo Hashimoto, Kaoru Kahata, Katsuya Fujimoto, Tomoyuki Endo, Chikara Shimizu, Takanori Teshima

  Journal of clinical apheresis 35 (5) 413 - 419 2020/09 

  BACKGROUND: Pegfilgrastim has equivalent efficacy to daily granulocyte colony-stimulating factor (G-CSF) in enhancing neutrophil recovery after chemotherapy, but data on its use for peripheral blood stem cell (PBSC) mobilization are limited. We evaluated the safety and efficacy of CD34+ PBSC mobilization by low-dose (3.6 mg) pegfilgrastim after chemotherapy in patients with malignant lymphoma. STUDY DESIGN AND METHODS: Twenty patients with malignant lymphoma were enrolled in this study. Cytotoxic chemotherapy was started on day 1, and 3.6 mg of pegfilgrastim was subcutaneously administered on day 7. CD34+ cells were counted in the peripheral blood daily from days 11 to 14 using a flow cytometric analysis. RESULTS: In 19 of the 20 patients (95%), the CD34+ cell counts in the peripheral blood exceeded 10 × 106/L, with a mean value of 20.3 on day 11, 38.0 on day 12, 40.3 on day 13, and 40.1 on day 14. Older age was associated with lower maximum CD34+ cell mobilization. The most frequent adverse events associated with pegfilgrastim were back pain, nausea, appetite loss, and lactate dehydrogenase elevation. CONCLUSION: Our data indicated that a single dose of 3.6 mg pegfilgrastim on day 7 after chemotherapy safely and effectively mobilized CD34+ cells.
• Immune checkpoint blockade in allogeneic hematopoietic cell transplantation

  Daigo Hashimoto

  Journal of Hematopoietic Cell Transplantation 9 (1) 13 - 22 2020/09 [Refereed][Invited]
  
• Intestinal goblet cells protect against GVHD after allogeneic stem cell transplantation via Lypd8.

  Takahide Ara, Daigo Hashimoto, Eiko Hayase, Clara Noizat, Ryo Kikuchi, Yuta Hasegawa, Kana Matsuda, Shoko Ono, Yoshihiro Matsuno, Ko Ebata, Reiki Ogasawara, Shuichiro Takahashi, Hiroyuki Ohigashi, Emi Yokoyama, Keitaro Matsuo, Junichi Sugita, Masahiro Onozawa, Ryu Okumura, Kiyoshi Takeda, Takanori Teshima

  Science translational medicine 12 (550) 2020/07/01 [Refereed][Not invited]
   

  Graft-versus-host disease (GVHD) and infection are major obstacles to successful allogeneic hematopoietic stem cell transplantation (HSCT). Intestinal goblet cells form the mucus layers, which spatially segregate gut microbiota from host tissues. Although it is well known that goblet cell loss is one of the histologic features of GVHD, effects of their loss in pathophysiology of GVHD remain to be elucidated. In mouse models of allogeneic HSCT, goblet cells in the colon were significantly reduced, resulting in disruption of the inner mucus layer of the colon and increased bacterial translocation into colonic mucosa. Pretransplant administration of interleukin-25 (IL-25), a growth factor for goblet cells, protected goblet cells against GVHD, prevented bacterial translocation, reduced plasma concentrations of interferon-γ (IFN-γ) and IL-6, and ameliorated GVHD. The protective role of IL-25 was dependent on Lypd8, an antimicrobial molecule produced by enterocytes in the colon that suppresses motility of flagellated bacteria. In clinical colon biopsies, low numbers of goblet cells were significantly associated with severe intestinal GVHD, increased transplant-related mortality, and poor survival after HSCT. Goblet cell loss is associated with poor transplant outcome, and administration of IL-25 represents an adjunct therapeutic strategy for GVHD by protecting goblet cells.
• Short-term treatment with imetelstat sensitizes hematopoietic malignant cells to a genotoxic agent via suppression of the telomerase-mediated DNA repair process.

  Daisuke Hidaka, Masahiro Onozawa, Naohiro Miyashita, Shota Yokoyama, Masao Nakagawa, Daigo Hashimoto, Takanori Teshima

  Leukemia & lymphoma 61 (11) 1 - 11 2020/06/22 [Refereed][Not invited]
   

  Imetelstat is a specific and competitive inhibitor of telomerase enzymatic activity. We demonstrated that imetelstat could interfere with the DNA repair process and enhance the effect of DNA damaging agents using hematological tumor cell lines. Short-term administration of imetelstat enhanced growth suppression by anticancer agents and radiation. It also upregulated γH2AX expression induced by irradiation. Immunofluorescence staining showed that both human telomerase reverse transcriptase (hTERT) and γH2AX were upregulated and co-localized in the nucleus of peripheral blood mononuclear cells after irradiation, suggesting that hTERT was involved in the DNA-DSB repair process. Imetelstat enhanced growth inhibitory effect of cytotoxic agents in short-term culture without shortening of telomeres, indicating that this effect was attributed by telomere length independent mechanism. Our results suggest that the combination of short-term treatment with imetelstat and cytotoxic agent is a promising strategy to treat a wide variety of hematopoietic malignancies.
• High metabolic heterogeneity on baseline 18FDG-PET/CT scan as a poor prognostic factor for newly diagnosed diffuse large B-cell lymphoma.

  Hajime Senjo, Kenji Hirata, Koh Izumiyama, Koichiro Minauchi, Eriko Tsukamoto, Kazuo Itoh, Minoru Kanaya, Akio Mori, Shuichi Ota, Daigo Hashimoto, Takanori Teshima

  Blood advances 4 (10) 2286 - 2296 2020/05/26 [Refereed][Not invited]
   

  Metabolic heterogeneity (MH) can be measured using 18F-fluorodeoxyglucose (18FDG) positron emission tomography/computed tomography (PET/CT), and it indicates an inhomogeneous tumor microenvironment. High MH has been shown to predict a worse prognosis for primary mediastinal B-cell lymphoma, whereas its prognostic value in diffuse large B-cell lymphoma (DLBCL) remains to be determined. In the current study, we investigated the prognostic values of MH evaluated in newly diagnosed DLBCL. In the training cohort, 86 patients treated with cyclophosphamide, doxorubicin, vincristine, and prednisone-like chemotherapies were divided into low-MH and high-MH groups using receiver operating characteristic analysis. MH was not correlated with metabolic tumor volume of the corresponding lesion, indicating that MH was independent of tumor burden. At 5 years, overall survivals were 89.5% vs 61.2% (P = .0122) and event-free survivals were 73.1% vs 51.1% (P = .0327) in the low- and high-MH groups, respectively. A multivariate Cox-regression analysis showed that MH was an independent predictive factor for overall survival. The adverse prognostic impacts of high MH were confirmed in an independent validation cohort with 64 patients. In conclusion, MH on baseline 18FDG-PET/CT scan predicts treatment outcomes for patients with newly diagnosed DLBCL.
• Histological and magnified endoscopic evaluation of villous atrophy in gastrointestinal graft-versus-host disease.

  Kana Matsuda, Shoko Ono, Ikko Tanaka, Masaki Inoue, Sayoko Kinowaki, Marin Ishikawa, Momoko Tsuda, Keiko Yamamoto, Yuichi Shimizu, Shuichiro Takahashi, Eiko Hayase, Daigo Hashimoto, Takanori Teshima, Naoya Sakamoto

  Annals of hematology 99 (5) 1121 - 1128 2020/05 [Refereed][Not invited]
   

  AIM:  To measure histological villous atrophy and to clarify the diagnostic accuracy of endoscopic villous atrophy in gastrointestinal graft-versus-host disease. METHODS:  Data for patients who underwent upper and/or lower endoscopic examinations after hematopoietic stem cell transplantation were retrospectively collected. In study 1, group A included 56 patients in whom GI-GVHD was histologically confirmed and group B included 60 patients in whom GI-GVHD was not histologically confirmed. Group C included 59 patients before HSCT. The lengths of villi and crypts in the duodenum and terminal ileum were histologically measured. In study 2, the diagnostic accuracies of villous atrophy of the duodenum and of the terminal ileum using magnifying endoscopy were evaluated. RESULTS:  In study 1, the lengths of villi and the villi/crypt (V/C) ratios of the duodenum and terminal ileum in group A were significantly smaller than those in the other groups (p < 0.05). V/C ratio was moderately correlated with clinical severity, histological grades, and endoscopic grades in the terminal ileum. In study 2, the diagnostic accuracies of magnified images for villous atrophy were 83.8% in the duodenum and 94.9% in the terminal ileum. CONCLUSION:  Magnifying endoscopy enables evaluation of villous atrophy and is useful for optical biopsy of GVHD.
• Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone combined with high-dose methotrexate plus intrathecal chemotherapy for newly diagnosed intravascular large B-cell lymphoma (PRIMEUR-IVL): a multicentre, single-arm, phase 2 trial.

  Kazuyuki Shimada, Motoko Yamaguchi, Yoshiko Atsuta, Kosei Matsue, Keijiro Sato, Shigeru Kusumoto, Hirokazu Nagai, Jun Takizawa, Noriko Fukuhara, Koji Nagafuji, Kana Miyazaki, Eiichi Ohtsuka, Masataka Okamoto, Yasumasa Sugita, Toshiki Uchida, Satoshi Kayukawa, Atsushi Wake, Daisuke Ennishi, Yukio Kondo, Tohru Izumi, Yoshihiro Kin, Kunihiro Tsukasaki, Daigo Hashimoto, Masaaki Yuge, Atsumi Yanagisawa, Yachiyo Kuwatsuka, Satoko Shimada, Yasufumi Masaki, Nozomi Niitsu, Hitoshi Kiyoi, Ritsuro Suzuki, Takashi Tokunaga, Shigeo Nakamura, Tomohiro Kinoshita

  The Lancet. Oncology 21 (4) 593 - 602 2020/04 [Refereed][Not invited]
   

  BACKGROUND: Intravascular large B-cell lymphoma (IVLBCL) is a rare disease for which there is no available standard treatment. We aimed to ascertain the safety and activity of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) with high-dose methotrexate and intrathecal chemotherapy as CNS-oriented therapy for patients with previously untreated IVLBCL. METHODS: PRIMEUR-IVL is a multicentre, single-arm, phase 2 trial at 22 hospitals in Japan. Eligible patients had untreated histologically confirmed IVLBCL, were aged 20-79 years, had an Eastern Cooperative Group performance status of 0-3, and had no apparent CNS involvement at diagnosis. Patients received three cycles of R-CHOP (rituximab 375 mg/m2 intravenously on day 1 [except cycle one, which was on day 8]; cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 [maximum 2·0 mg] intravenously on day 1 of cycle one and day 2 of cycles two and three; and prednisolone 100 mg/day orally on days 1-5 of cycle one and days 2-6 of cycles two and three) followed by two cycles of rituximab with high-dose methotrexate (3·5 g/m2 intravenously on day 2 of cycles four and five) every 2 weeks and three additional cycles of R-CHOP. Intrathecal chemotherapy (methotrexate 15 mg, cytarabine 40 mg, and prednisolone 10 mg) was administered four times during the R-CHOP phase. The primary endpoint was 2-year progression-free survival. Efficacy analyses were done in all enrolled patients; safety analyses were done in all enrolled and treated patients. The trial is registered in the UMIN Clinical Trials Registry (UMIN000005707) and the Japan Registry of Clinical Trials (jRCTs041180165); the trial is ongoing for long-term follow-up. FINDINGS: Between June 16, 2011, and July 21, 2016, 38 patients were enrolled, of whom 37 were eligible; one patient was excluded because of a history of testicular lymphoma. Median follow-up was 3·9 years (IQR 2·5-5·5). 2-year progression-free survival was 76% (95% CI 58-87). The most frequent adverse events of grade 3-4 were neutropenia and leucocytopenia, which were reported in all 38 (100%) patients. Serious adverse events were hypokalaemia, febrile neutropenia with hypotension, hypertension, and intracerebral haemorrhage (reported in one [3%] patient each). No treatment-related deaths occurred during protocol treatment. INTERPRETATION: R-CHOP combined with rituximab and high-dose methotrexate plus intrathecal chemotherapy is a safe and active treatment for patients with IVLBCL without apparent CNS involvement at diagnosis, and this regimen warrants future investigation. FUNDING: The Japan Agency for Medical Research and Development, the Center for Supporting Hematology-Oncology Trials, and the National Cancer Center.
• Short-term KRP203 and posttransplant cyclophosphamide for graft-versus-host disease prophylaxis.

  Emi Yokoyama, Daigo Hashimoto, Eiko Hayase, Takahide Ara, Reiki Ogasawara, Shuichiro Takahashi, Hiroyuki Ohigashi, Takahiro Tateno, Yuta Hasegawa, Xuanzhong Chen, Takanori Teshima

  Bone marrow transplantation 55 (4) 787 - 795 2020/04 [Refereed][Not invited]
   

  Posttransplant high-dose cyclophosphamide (PTCY) has been increasingly used as graft-versus-host disease (GVHD) prophylaxis after HLA-haploidentical or matched hematopoietic stem cell transplantation (SCT). However, PTCY alone is insufficient and requires additional immunosuppressants such as calcineurin inhibitors. In the current study, we evaluated effects of a novel GVHD prophylaxis with PTCY in combination with short-term KRP203, a selective agonist of sphingosine-1-phosphate receptor 1 that regulates egress of lymphocytes from the secondary lymphoid organs (SLOs) in mice. Short-term oral administration of KRP203 alone induced apoptosis of donor T cells in the SLOs and ameliorated GVHD. Administration of KRP203 significantly preserved graft-versus-leukemia effects compared to cyclosporin. A combination of KRP203 on days 0 to +4 and PTCY on day +3 synergistically suppressed donor T-cell migration into the intestine and skin, and ameliorated GVHD more potently than PTCY alone. A combination of short-term KRP203 and PTCY is a promising novel calcineurin-free GVHD prophylaxis in HLA-haploidentical SCT.
• Reduced dose of MTX for GVHD prophylaxis promotes engraftment and decreases non-relapse mortality in umbilical cord blood transplantation.

  Souichi Shiratori, Hiroyuki Ohigashi, Shuichiro Takahashi, Takahide Ara, Hideki Goto, Masao Nakagawa, Junichi Sugita, Masahiro Onozawa, Kaoru Kahata, Tomoyuki Endo, Daigo Hashimoto, Takanori Teshima

  Annals of hematology 99 (3) 591 - 598 2020/03 [Refereed][Not invited]
   

  Although a combination of calcineurin inhibitor and methotrexate (MTX) is used for graft-versus-host disease (GVHD) prophylaxis in umbilical cord blood transplantation (CBT), optimal dose of MTX for CBT remains to be determined.We conducted a retrospective study to evaluate the safety and efficacy of standard-dose MTX (St-MTX, 15 mg/m2 on day 1 and 10 mg/m2 on days 3 and 6) and mini-dose MTX (Mini-MTX, 5 mg/m2 on days 1, 3 and 6) for GVHD prophylaxis in patients who underwent single unit CBT against hematological malignancies.Thirty-two and 26 patients received St-MTX and Mini-MTX, respectively. Cumulative incidence of neutrophil engraftment was significantly higher in the Mini-MTX group than in the St-MTX group (88.5% vs 65.6%, P = 0.00448). Cumulative incidences of grade II to IV and grade III to IV of acute graft-versus-host disease (GVHD) were 34.4% and 6.2% in the St-MTX group, and 34.6% and 7.7% in the Mini-MTX group with no statistical significance. One-year non-relapse mortality (NRM) was significantly lower in the Mini-MTX group compared to the St-MTX group (31.2% vs 3.8%, P = 0.00938), whereas relapse rate was not different between the groups. Multivariate analysis also indicated that Mini-MTX significantly improved engraftment (HR, 0.5359; 95% CI, 0.3082 to 0.9318; P = 0.0270) and reduced NRM (HR, 0.117; 95% CI, 0.0151 to 0.9067; P = 0.040).Our study suggests that GVHD prophylaxis using Mini-MTX in CBT is feasible and associated with improvement of engraftment and reduction in NRM.
• Loss of nivolumab binding to T cell PD-1 predicts relapse of Hodgkin lymphoma.

  Reiki Ogasawara, Daigo Hashimoto, Junichi Sugita, Fumihiko Yamawaki, Tomoaki Naka, Tomoko Mitsuhashi, Shuichiro Takahashi, Naohiro Miyashita, Kohei Okada, Masahiro Onozawa, Yoshihiro Matsuno, Takanori Teshima

  International journal of hematology 111 (3) 475 - 479 0925-5710 2020/03 [Refereed][Not invited]
   

  Nivolumab is effective in the treatment of classical Hodgkin lymphoma that relapsed after allogeneic hematopoietic stem cell transplantation (SCT) with the risk of graft-versus-host disease; however, the optimal time and dose of nivolumab administration remain to be investigated. Nivolumab binding to PD-1 masks flowcytometric detection of PD-1 by the anti-PD-1 monoclonal antibody EH12.1. Using this method, we monitored nivolumab binding on T cells after nivolumab treatment in a patient with classical Hodgkin lymphoma relapsed after allogeneic SCT. Nivolumab was effective while prolonged nivolumab binding was evident, but restoration of PD-1 staining predicted tumor relapse. Flowcytometric monitoring of nivolumab binding on T cells could be a promising biomarker for predicting tumor relapse and determining the timing of nivolumab administration.
• Microbiota as Predictor of Mortality in Allogeneic Hematopoietic-Cell Transplantation.

  Jonathan U Peled, Antonio L C Gomes, Sean M Devlin, Eric R Littmann, Ying Taur, Anthony D Sung, Daniela Weber, Daigo Hashimoto, Ann E Slingerland, John B Slingerland, Molly Maloy, Annelie G Clurman, Christoph K Stein-Thoeringer, Kate A Markey, Melissa D Docampo, Marina Burgos da Silva, Niloufer Khan, André Gessner, Julia A Messina, Kristi Romero, Meagan V Lew, Amy Bush, Lauren Bohannon, Daniel G Brereton, Emily Fontana, Luigi A Amoretti, Roberta J Wright, Gabriel K Armijo, Yusuke Shono, Míriam Sanchez-Escamilla, Nerea Castillo Flores, Ana Alarcon Tomas, Richard J Lin, Lucrecia Yáñez San Segundo, Gunjan L Shah, Christina Cho, Michael Scordo, Ioannis Politikos, Kasumi Hayasaka, Yuta Hasegawa, Boglarka Gyurkocza, Doris M Ponce, Juliet N Barker, Miguel-Angel Perales, Sergio A Giralt, Robert R Jenq, Takanori Teshima, Nelson J Chao, Ernst Holler, Joao B Xavier, Eric G Pamer, Marcel R M van den Brink

  The New England journal of medicine 382 (9) 822 - 834 2020/02/27 [Refereed][Not invited]
   

  BACKGROUND: Relationships between microbiota composition and clinical outcomes after allogeneic hematopoietic-cell transplantation have been described in single-center studies. Geographic variations in the composition of human microbial communities and differences in clinical practices across institutions raise the question of whether these associations are generalizable. METHODS: The microbiota composition of fecal samples obtained from patients who were undergoing allogeneic hematopoietic-cell transplantation at four centers was profiled by means of 16S ribosomal RNA gene sequencing. In an observational study, we examined associations between microbiota diversity and mortality using Cox proportional-hazards analysis. For stratification of the cohorts into higher- and lower-diversity groups, the median diversity value that was observed at the study center in New York was used. In the analysis of independent cohorts, the New York center was cohort 1, and three centers in Germany, Japan, and North Carolina composed cohort 2. Cohort 1 and subgroups within it were analyzed for additional outcomes, including transplantation-related death. RESULTS: We profiled 8767 fecal samples obtained from 1362 patients undergoing allogeneic hematopoietic-cell transplantation at the four centers. We observed patterns of microbiota disruption characterized by loss of diversity and domination by single taxa. Higher diversity of intestinal microbiota was associated with a lower risk of death in independent cohorts (cohort 1: 104 deaths among 354 patients in the higher-diversity group vs. 136 deaths among 350 patients in the lower-diversity group; adjusted hazard ratio, 0.71; 95% confidence interval [CI], 0.55 to 0.92; cohort 2: 18 deaths among 87 patients in the higher-diversity group vs. 35 deaths among 92 patients in the lower-diversity group; adjusted hazard ratio, 0.49; 95% CI, 0.27 to 0.90). Subgroup analyses identified an association between lower intestinal diversity and higher risks of transplantation-related death and death attributable to graft-versus-host disease. Baseline samples obtained before transplantation already showed evidence of microbiome disruption, and lower diversity before transplantation was associated with poor survival. CONCLUSIONS: Patterns of microbiota disruption during allogeneic hematopoietic-cell transplantation were similar across transplantation centers and geographic locations; patterns were characterized by loss of diversity and domination by single taxa. Higher diversity of intestinal microbiota at the time of neutrophil engraftment was associated with lower mortality. (Funded by the National Cancer Institute and others.).
• Salvage Transplantation with Cord Blood for Graft Rejection of Peripheral Blood Stem Cells due to Donor Specific Antibody

  Maria Regina Pelobello de Leon, Shuichiro Takahashi, Masahiro Onozawa, Makoto Ito, Manabu Nakano, Hajime Senjo, Masahiro Chiba, Hiroyuki Ohigashi, Emi Yokoyama, Junichi Sugita, Daigo Hashimoto, Takanori Teshima

  BLOOD CELL THERAPY / The official journal of APBMT 3 (3) 74 - 77 2020 [Refereed][Not invited]
   

  Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapy for various kinds of hematological malignancies and disorders. Recently, HLA-haploidentical stem cell transplantation with post-transplantation cyclophosphamide (PTCy-haplo HSCT) has been widely performed due to its safety and favorable immune recovery. However, graft rejection remains an obstacle to PTCy-haplo HSCT. Donor specific antibody (DSA) is considered to be a major factor of graft rejection of haplo HSCT. We herein present a case of graft rejection after PTCy haplo-HSCT due to DSA induced by pretransplant platelet transfusion after donor selection. The patient was dependent on platelet transfusion and had not received cytotoxic chemotherapy because he was diagnosed as myelodysplastic syndrome/myeloproliferative neoplasm-unclassifiable. We retrospectively confirmed the level of DSA just before the first transplantation and found that it was dramatically elevated, which was enough to cause graft rejection. We successfully performed cord blood transplantation of the HLA that was not the target of DSA, as salvage transplantation without any desensitization. This case illustrates that we have to confirm the presence of DSA immediately before the haplo-HSCT, particularly in high risk patients who are dependent on platelet transfusion and have no cytotoxic chemotherapy before HSCT.
• [Animal models in the study of allogeneic hematopoietic stem cell transplantation].

  Daigo Hashimoto

  [Rinsho ketsueki] The Japanese journal of clinical hematology 61 (4) 369 - 378 2020 [Refereed][Not invited]
   

  For the past seven decades, animal models of allogeneic hematopoietic stem cell transplantation (SCT) have contributed to the development of clinical SCT. Murine models are particularly useful to study the pathophysiology of graft-versus-host disease (GVHD) and the mechanism of graft-versus-leukemia (GVL) effects after SCT because of the variety of genetically engineered mice and numerous research reagents for immune profiling. SCT models using non-human primates are useful in preclinical studies to evaluate the efficacy and safety of novel therapies developed in murine models. In the present manuscript, the advantage and disadvantages of each animal SCT model is discussed, mainly focusing on the studies of GVHD and GVL effects.
• [Graft-versus-host disease: new insights into disease pathogenesis].

  Daigo Hashimoto

  [Rinsho ketsueki] The Japanese journal of clinical hematology 61 (8) 959 - 964 2020 [Refereed][Not invited]
   

  Graft-versus-host disease (GVHD) is a potentially life-threatening complication associated with allogeneic hematopoietic stem cell transplantation (allo-SCT). Although prophylaxis and GVHD treatment using immunosuppressants are essential for a successful allo-SCT, profound immunosuppression could lead to an infection and/or the recurrence of malignant diseases. Recently, the concept of tissue tolerance has emerged. This concept has been identified as a means to suppress GVHD by relying on tissue-intrinsic mechanisms that are independent from those underlying immune tolerance. Thus, GVHD prophylaxis and treatments targeting the mechanisms that promote tissue tolerance could help suppress GVHD and maintain leukocyte-mediated immune responses against tumors and infectious pathogens. Epithelial regeneration from LGR5-positive intestinal stem cells and epithelial maintenance mediated by metabolites from the intestinal microbiota are representative mechanisms that promote tissue tolerance in the gut. However, these protective mechanisms are weakened by GVHD and conditioning regimens. This review focuses on the pathophysiology of acute GVHD and tissue-intrinsic mechanisms that promote tissue tolerance.
• Myeloid differentiation factor 88 signaling in donor T cells accelerates graft-versus-host disease.

  Satomi Matsuoka, Daigo Hashimoto, Masanori Kadowaki, Hiroyuki Ohigashi, Eiko Hayase, Emi Yokoyama, Yuta Hasegawa, Takahiro Tateno, Xuanzhong Chen, Kazutoshi Aoyama, Hideyo Oka, Masahiro Onozawa, Kiyoshi Takeda, Koichi Akashi, Takanori Teshima

  Haematologica 105 (1) 226 - 234 2020/01 [Refereed][Not invited]
   

  Myeloid differentiation factor 88 (MyD88) signaling has a crucial role in activation of both innate and adoptive immunity. MyD88 transduces signals via Toll-like receptor and interleukin-1 receptor superfamily to the NFκB pathway and inflammasome by forming a molecular complex with interleukin-1 receptor-associated kinase 4. The MyD88/interleukin-1 receptor-associated kinase 4 pathway plays an important role, not only in innate immunity, but also T-cell immunity; however, its role in donor T cells on the pathophysiology of graft-versus-host disease (GvHD) remains to be elucidated. We addressed this issue by using MyD88-deficient T cells in a mouse model of allogeneic hematopoietic stem cell transplantation (allo-SCT). While MyD88-deficient and wild-type T cells proliferated equivalently after transplantation, MyD88-deficient T cells demonstrated impaired survival and differentiation toward Th1, Tc1, and Th17, and induced less severe GvHD compared to wild-type T cells. Administration of interleukin-1 receptor-associated kinase 4 inhibitor PF-06650833 significantly ameliorated GvHD after allo-SCT. These results thus demonstrate that donor T-cell MyD88/interleukin-1 receptor-associated kinase 4 pathway is a novel therapeutic target against GvHD after allo-SCT.
• Lactose drives Enterococcus expansion to promote graft-versus-host disease.

  C K Stein-Thoeringer, K B Nichols, A Lazrak, M D Docampo, A E Slingerland, J B Slingerland, A G Clurman, G Armijo, A L C Gomes, Y Shono, A Staffas, M Burgos da Silva, S M Devlin, K A Markey, D Bajic, R Pinedo, A Tsakmaklis, E R Littmann, A Pastore, Y Taur, S Monette, M E Arcila, A J Pickard, M Maloy, R J Wright, L A Amoretti, E Fontana, D Pham, M A Jamal, D Weber, A D Sung, D Hashimoto, C Scheid, J B Xavier, J A Messina, K Romero, M Lew, A Bush, L Bohannon, K Hayasaka, Y Hasegawa, M J G T Vehreschild, J R Cross, D M Ponce, M A Perales, S A Giralt, R R Jenq, T Teshima, E Holler, N J Chao, E G Pamer, J U Peled, M R M van den Brink

  Science (New York, N.Y.) 366 (6469) 1143 - 1149 2019/11/29 [Refereed][Not invited]
   

  Disruption of intestinal microbial communities appears to underlie many human illnesses, but the mechanisms that promote this dysbiosis and its adverse consequences are poorly understood. In patients who received allogeneic hematopoietic cell transplantation (allo-HCT), we describe a high incidence of enterococcal expansion, which was associated with graft-versus-host disease (GVHD) and mortality. We found that Enterococcus also expands in the mouse gastrointestinal tract after allo-HCT and exacerbates disease severity in gnotobiotic models. Enterococcus growth is dependent on the disaccharide lactose, and dietary lactose depletion attenuates Enterococcus outgrowth and reduces the severity of GVHD in mice. Allo-HCT patients carrying lactose-nonabsorber genotypes showed compromised clearance of postantibiotic Enterococcus domination. We report lactose as a common nutrient that drives expansion of a commensal bacterium that exacerbates an intestinal and systemic inflammatory disease.
• Unusual computed tomography findings of acute eosinophilic pneumonia after cord blood transplantation.

  Hajime Senjo, Daigo Hashimoto

  International journal of hematology 110 (4) 387 - 388 2019/10 [Refereed][Not invited]
  
• Safety and efficacy of amnion-derived mesenchymal stem cells (AM01) in patients with steroid-refractory acute graft-versus-host disease after allogeneic haematopoietic stem cell transplantation: a study protocol for a phase I/II Japanese trial.

  Kenichi Yamahara, Akiko Hamada, Toshihiro Soma, Rika Okamoto, Masaya Okada, Satoshi Yoshihara, Kyoko Yoshihara, Kazuhiro Ikegame, Hiroya Tamaki, Katsuji Kaida, Takayuki Inoue, Yuko Ohsugi, Hiroki Nishikawa, Hiroshi Hayashi, Yoichi M Ito, Hiroaki Iijima, Shunsuke Ohnishi, Daigo Hashimoto, Toshiyuki Isoe, Takanori Teshima, Hiroyasu Ogawa, Norihiro Sato, Yoshihiro Fujimori

  BMJ open 9 (7) e026403  2019/07/09 [Refereed][Not invited]
   

  INTRODUCTION: Regenerative medicine and cell therapies have been gaining much attention among clinicians. Therapeutic infusion of mesenchymal stromal cells (MSCs) is now a leading investigational strategy for the treatment of acute graft-versus-host disease (aGVHD). Bone marrow MSCs are approved for manufacture and marketing as a cell therapy for aGVHD. Our non-clinical studies confirmed that human amnion-derived MSCs had immunomodulatory activity equal to or higher than that of human bone marrow MSCs. This study will aim to evaluate the safety and efficacy of amnion-derived MSCs (AM01) in patients with steroid-refractory aGVHD. METHODS AND ANALYSIS: This study will be a multicentre, single-arm, open-label trial (an interventional study). This clinical trial will begin with a low-dose group, and when safety has been confirmed in at least three cases in the low-dose group, treatment will begin for the high-dose group, for which the safety will also be verified. The primary endpoint is to assess the safety of intravenous infusion therapy of AM01 within 24 hours after intravenous infusion of AM01. The secondary endpoint is to explore the efficacy of intravenous infusion therapy with AM01. ETHICS AND DISSEMINATION: The institutional review boards of all participating hospitals approved this study protocol (latest V3.3.0, 3 August 2018). Final data will be publicly announced. A report releasing the study results will be submitted for publication to an appropriate peer-reviewed journal. TRIAL REGISTRATION NUMBER: UMIN000029945.
• Ocular instillation of vitamin A-coupled liposomes containing HSP47 siRNA ameliorates dry eye syndrome in chronic GVHD.

  Hiroyuki Ohigashi, Daigo Hashimoto, Eiko Hayase, Shuichiro Takahashi, Takahide Ara, Tomohiro Yamakawa, Junichi Sugita, Masahiro Onozawa, Masao Nakagawa, Takanori Teshima

  Blood advances 3 (7) 1003 - 1010 2019/04/09 [Refereed][Not invited]
   

  Chronic graft-versus-host disease (GVHD) profoundly affects the quality of life of long-term survivors of allogeneic hematopoietic stem cell transplantation (SCT). The eyes are frequently involved, and dry eye syndrome is the most common manifestation of ocular chronic GVHD. We explored the role of heat shock protein 47 (HSP47) in ocular GVHD and developed a novel antifibrotic topical therapy using vitamin A-coupled liposomes containing HSP47 small interfering RNA (siRNA) against HSP47 (VA-lip HSP47). In a mouse model of chronic GVHD, infiltration of HSP47+ fibroblasts and massive fibrosis surrounding the lacrimal ducts were observed after allogeneic SCT, leading to impaired tear secretion. After ocular instillation, VA-lip HSP47 was distributed to the lacrimal glands, knocked down HSP47 expression in fibroblasts, reduced collagen deposition, and restored tear secretion after allogeneic SCT. Ocular instillation of VA-lip HSP47 also ameliorated established lacrimal gland fibrosis and dry eye syndrome. VA-lip HSP47 eye drops are a promising prophylactic and therapeutic option against dry eye syndrome in chronic GVHD.
• 生物由来原料基準を満たす国産ウシ血小板溶解物「NeoSERA」を原材料とする羊膜由来間葉系幹細胞の細胞製剤化

  山原 研一, 浜田 彰子, 黒田 将子, 池本 純子, 吉原 享子, 吉原 哲, 岡田 昌也, 橋本 大吾, 相馬 俊裕, 豊嶋 崇徳, 藤盛 好啓

  日本輸血細胞治療学会誌 (一社)日本輸血・細胞治療学会 65 (2) 476 - 476 1881-3011 2019/04
• Serum level of soluble interleukin-2 receptor is positively correlated with metabolic tumor volume on 18 F-FDG PET/CT in newly diagnosed patients with diffuse large B-cell lymphoma.

  Hajime Senjo, Minoru Kanaya, Koh Izumiyama, Koichiro Minauchi, Kenji Hirata, Akio Mori, Makoto Saito, Masanori Tanaka, Hiroaki Iijima, Eriko Tsukamoto, Kazuo Itoh, Shuichi Ota, Masanobu Morioka, Daigo Hashimoto, Takanori Teshima

  Cancer medicine 8 (3) 953 - 962 2019/03 [Refereed][Not invited]
   

  Diffuse large B-cell lymphoma (DLBCL) is the most frequent subtype of non-Hodgkin lymphoma. High total metabolic tumor volume (TMTV) calculated using 18 F-FDG PET/CT images at diagnosis predicts poor prognosis of patients with DLBCL. However, high cost and poor access to the imaging facilities hamper wider use of 18 F-FDG PET/CT. In order to explore a surrogate marker for TMTV, we evaluated the correlation between the serum levels of soluble interleukin-2 receptor (sIL-2R) and TMTV in 64 patients with DLBCL, and the results were verified in an independent validation cohort of 86 patients. Serum levels of sIL-2R were significantly correlated with TMTV. ROC analysis revealed that the cutoff value of TMTV ≥150 cm3 or sIL-2R ≥ 1300 U/mL could predict failure to achieve EFS24 with areas under the curve (AUC) 0.706 and 0.758, respectively. Each of TMTV ≥150 cm3 and sIL-2R ≥1300 U/mL was significantly associated with worse 5-year overall survival and event-free survival. Importantly, each of sIL-2R <1300 U/mL or TMTV <150 cm3 identified patients with favorable prognosis among NCCN-IPI high-intermediate and high-risk group. Serum level of sIL-2R represents a convenient surrogate marker to estimate metabolic tumor burden measured by 18 F-FDG PET/CT that can predict treatment outcomes of patients with DLBCL.
• UTILITY OF LISS AS AN AUTOANTIBODY ADSORPTION METHOD FOR DETECTION OF COEXISTING ALLOANTIBODIES IN PATIENTS WITH AUTOANTIBODIES

  Takayo Uwatoko, Chiaki Watanabe, Makoto Ito, Ryo Uozumi, Yasuhiro Hayashi, Shuichiro Takahashi, Naohiro Miyashita, Souichi Shiratori, Daigo Hashimoto, Junichi Sugita, Eiko Hayase, Koji Akizawa, Takanori Teshima

  Japanese Journal of Transfusion and Cell Therapy 65 (1) 98 - 102 1881-3011 2019/02/28
• 自己抗体保有患者の同種抗体検出におけるLISSを用いた自己抗体吸着法の有用性の検討

  上床 貴代, 渡邊 千秋, 伊藤 誠, 魚住 諒, 林 泰弘, 高橋 秀一郎, 宮下 直洋, 白鳥 聡一, 橋本 大吾, 杉田 純一, 早瀬 英子, 秋沢 宏次, 豊嶋 崇徳

  日本輸血細胞治療学会誌 (一社)日本輸血・細胞治療学会 65 (1) 98 - 102 1881-3011 2019/02 

  <背景>自己抗体保有患者は自己抗体の他に同種抗体を保有する頻度が多いため、共存する同種抗体の検出が重要となる。ポリエチレングリコール(PEG)吸着法は自己抗体吸着法として一般的に用いられているが、低力価の同種抗体も吸着されると指摘する報告がある。海外では低イオン強度溶液(low ionic strength solution;LISS)を用いた自己抗体吸着法(以下LISS吸着法)も短時間での自己抗体吸着において有用であるという報告があるが本邦では一般的ではない。今回我々はLISS吸着法が同種抗体の検出に有用であった3症例を経験したので報告する。<方法>自己抗体を保有する3患者においてLISS吸着法を行った。3ヵ月以内に輸血歴のない患者は自己赤血球を用い、輸血歴のある患者は患者とRh、Kidd、Diego同型の酵素処理した他家赤血球を用いて自己抗体の吸着を行い、上清で同種抗体の検索を行った。<結果>3例共にLISS吸着法にて同種抗体が検出された。<考察>LISS吸着法は自己抗体の吸着および、共存する同種抗体の検出において有用であると考えられた。(著者抄録)
• [Niche signals regulate differentiation and functions of tissue resident macrophages]

  Daigo Hashimoto

  Rinsho Ketsueki 59 (10) 1886 - 1894 2018/10 [Refereed][Invited]
  
• Essential role of IFN-γ in T cell–associated intestinal inflammation

  Yoshihiro Eriguchi, Kiminori Nakamura, Yuki Yokoi, Rina Sugimoto, Shuichiro Takahashi, Daigo Hashimoto, Takanori Teshima, Tokiyoshi Ayabe, Michael E. Selsted, André J. Ouellette

  JCI Insight 3 (18) 2018/09/20 [Refereed][Not invited]
  
• 成人急性リンパ性白血病におけるIKZF1欠失およびCRLF2発現の解析(Analysis of IKZF1 deletion and CRLF2 expression in adult patients with acute lymphoblastic leukemia)

  橋口 淳一, 小野澤 真弘, 藤澤 真一, 高橋 秀一郎, 宮下 直洋, 早瀬 英子, 白鳥 聡一, 後藤 秀樹, 杉田 純一, 中川 雅夫, 橋本 大吾, 加畑 馨, 遠藤 知之, 山本 聡, 堤 豊, 長谷山 美仁, 永嶋 貴博, 盛 暁生, 太田 秀一, 宮城島 拓人, 柿木 康孝, 黒澤 光俊, 岩崎 博, 近藤 健, 豊嶋 崇徳

  臨床血液 59 (9) 1648 - 1648 0485-1439 2018/09
• Disseminated fusariosis emerged from prolonged local genital infection after cord blood transplantation

  Kohei Okada, Tomoyuki Endo, Daigo Hashimoto, Tomoyuki Saga, Takahide Ara, Reiki Ogasawara, Atsushi Yasumoto, Makoto Ibata, Mutsumi Takahata, Akio Shigematsu, Takeshi Kondo, Yasunori Muraosa, Toshifumi Nomura, Hiromi Kanno-Okada, Satoshi Hashino, Shinya Tanaka, Katsuhiko Kamei, Takanori Teshima

  Journal of Infection and Chemotherapy 24 (8) 660 - 663 1437-7780 2018/08/01 [Refereed][Not invited]
   

  Disseminated fusariosis (DF) is a rare life threatening fungal infection in immunocompromised hosts. We herein report a case of a fatal DF mimicking varicella zoster virus (VZV) infection that was emerged from a localized genital infection during cord blood transplantation (CBT) in a patient with severe aplastic anemia (SAA). The patient developed an ulcer following small painful vesicles mimics herpes simplex virus infection (HSV) on the glans penis before CBT, but a Fusarium species was identified. Despite administration of voriconazole, liposomal amphotericin B and granulocyte transfusion, the lesion was extended to extensive skin looked like VZV infection and the patients died after CBT. Massive fusarium infiltration was detected in multiple organs at autopsy. A genetic analysis of the mold identified Fusarium solani after his death. It should be noted that in patients with fusarium infection, localized and disseminated lesions of fusarium infection sometimes mimic HSV and VZV infections, which hampers an early diagnosis.
• Development of a Fluorescence in Situ Hybridization Probe for Detecting IKZF1 Deletion Mutations in Patients with Acute Lymphoblastic Leukemia

  Junichi Hashiguchi, Masahiro Onozawa, Satoshi Oguri, Shinichi Fujisawa, Masahisa Tsuji, Kohei Okada, Masao Nakagawa, Daigo Hashimoto, Kaoru Kahata, Takeshi Kondo, Chikara Shimizu, Takanori Teshima

  Journal of Molecular Diagnostics 20 (4) 446 - 454 1943-7811 2018/07/01 [Refereed][Not invited]
   

  Intragenic deletion of IKZF1 is a recurrent genomic alteration in acute lymphoblastic leukemia. The deletions are mediated by illegitimate variable(diversity)joining recombination via cryptic recombination signal sequences (RSSs). We developed a fluorescence in situ hybridization (FISH) probe set that can detect any type of IKZF1 deletion, including the commonly deleted exon 4 to 7 region. The probe set consists of a designed probe for the commonly deleted region (Cy3 red) and a bacterial artificial chromosomes clone probe for detecting the 3′ flanking region (Spectrum Green). Intact IKZF1 showed a fusion signal, and the deleted allele showed loss of the red signal (0R1G1F). The FISH probes worked correctly for human leukemic cell lines and clinical samples. One case showed an atypical break-apart signal (1R1G1F). Inverse PCR of the case revealed rearrangement of the excised IKZF1 fragment into a legitimate RSS site at Ig κ on chromosome 2, suggesting a pathogenic role of this recombination-activating gene 1/2-mediated event. In this study, we established FISH probe detecting IKZF1 deletion in a quick, quantitative, and cost-effective manner, and the results provided a novel insight into B-cell receptor editing by rearrangement of a cryptic RSS-mediated genomic fragment in acute lymphoblastic leukemia pathology.
• Intestinal Lymphatic Endothelial Cells Produce R-Spondin3.

  Ogasawara R, Hashimoto D, Kimura S, Hayase E, Ara T, Takahashi S, Ohigashi H, Yoshioka K, Tateno T, Yokoyama E, Ebata K, Kondo T, Sugita J, Onozawa M, Iwanaga T, Teshima T

  Scientific reports 8 (1) 10719 - 10719 2018/07 [Refereed][Not invited]
   

  The R-Spondin (R-Spo) family regulates WNT signaling and stimulates the proliferation and differentiation of intestinal stem cells (ISCs). R-Spo plays a critical role in maintaining intestinal homeostasis, but endogenous producers of R-Spo in the intestine remain to be investigated. We found that R-Spo3 was the major R-Spo family member produced in the intestine and it was predominantly produced by CD45-CD90+CD31+ lymphatic endothelial cells (LECs) in the lamina propria of the intestinal mucosa. Transcriptome analysis demonstrated that LECs highly expressed R-Spo receptor, Lgr5, suggesting an autocrine stimulatory loop in LECs. LECs were significantly reduced in number, and their R-Spo3 production was impaired in intestinal graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation. The impaired production of R-Spo3 in the intestine may be a novel mechanism of delayed tissue repair and defective mucosal defense in intestinal GVHD. We demonstrate a novel role of intestinal LECs in producing R-Spondin3 to maintain intestinal homeostasis.
• The association between the incidence of intestinal graft-vs-host disease and antibiotic use after allogeneic hematopoietic stem cell transplantation.

  Hidaka D, Hayase E, Shiratori S, Hasegawa Y, Ishio T, Tateno T, Okada K, Goto H, Sugita J, Onozawa M, Nakagawa M, Kahata K, Endo T, Hashimoto D, Teshima T

  Clinical transplantation 32 (9) e13361  0902-0063 2018/07 [Refereed][Not invited]
   

  Intestinal microbiota plays an important role in the regulation of allogeneic immune reaction after allogeneic hematopoietic stem cell transplantation (allo-SCT). Intestinal graft-vs-host disease (GVHD) is one of the major causes of mortality after allo-SCT and often complicated with intestinal dysbiosis. Recent studies suggest that antibiotic-induced dysbiosis is a risk factor for intestinal GVHD. We retrospectively evaluated the impacts of antibiotic use on the incidence of intestinal GVHD occurring before day 100 after allo-SCT. Among 213 patients who underwent allo-SCT, 200 patients achieving engraftment were analyzed. Antibiotics were classified into carbapenem, quinolone, penicillin, cephem, and glycopeptide. Among 128 patients who developed acute GVHD, intestinal GVHD developed in 36 patients. Patients with intestinal GVHD received significantly longer administration of carbapenem and glycopeptide compared to those without it in periengraftment period. In multivariate analysis, use of carbapenem for greater than 7 days was associated with an increased risk of intestinal GVHD. However, use of antibiotics for greater than 7 days was not associated with poor overall survival and high nonrelapse mortality. Long use of carbapenem in periengraftment period may be a risk for intestinal GVHD. Prospective studies are required to validate our findings.
• Wilms Tumor 1 Expression at Diagnosis Correlates With Genetic Abnormalities and Polymorphism But Is Not Independently Prognostic in Acute Myelogenous Leukemia: A Hokkaido Leukemia Net Study.

  Hidaka D, Onozawa M, Hashiguchi J, Miyashita N, Kasahara K, Fujisawa S, Hayase E, Okada K, Shiratori S, Goto H, Sugita J, Nakagawa M, Hashimoto D, Kahata K, Endo T, Yamamoto S, Tsutsumi Y, Haseyama Y, Nagashima T, Mori A, Ota S, Sakai H, Ishihara T, Imai K, Miyagishima T, Kakinoki Y, Kurosawa M, Kobayashi H, Iwasaki H, Shimizu C, Kondo T, Teshima T

  Clinical lymphoma, myeloma & leukemia 18 (11) e469-e479  2152-2650 2018/07 [Refereed][Not invited]
   

  BACKGROUND: The prognostic effect of Wilms tumor 1 (WT1) expression at the diagnosis of acute myelogenous leukemia (AML) has been controversial. The aim of the present study was to determine the correlations of WT1 expression at the diagnosis of AML with established prognostic alterations. PATIENTS AND METHODS: We analyzed diagnostic bone marrow samples from 252 patients. WT1 expression, single nucleotide polymorphism (SNP) in the WT1 gene (rs16754), and Fms-like tyrosine kinase receptor-3 internal tandem duplication (FLT3-ITD) mutation were analyzed for all patients. The nucleophosmin 1 (NPM1) mutation and CCAAT/enhancer-binding protein-α (CEBPA) double mutation were analyzed for cytogenetically normal (CN)-AML. The KIT mutation was analyzed for core-binding factor AML. RESULTS: Within the cytogenetically favorable prognosis group, WT1 expression in AML with inv(16) or t(15;17) was significantly greater than that in AML with t(8;21). In cases with CN-AML, FLT3-ITD and NPM1 mutations both correlated with greater expression of WT1, and the CEBPA double mutation was related to lower WT1 expression. The existence of both FLT3-ITD and NPM1 mutations showed synergistically greater expression of WT1 in CN-AML. SNP in the WT1 gene (rs16754) was significantly associated with lower expression of WT1. The WT1 levels were not prognostic factors in the total cohort or any cytogenetic group or stratified by SNP status. CONCLUSION: Because WT1 expression has correlated with known prognostic factors, the prognostic effect of WT1 levels could be misunderstood depending on the distribution of the collaborative mutations in each cohort. We have concluded that the prognostic significance of WT1 at the diagnosis of AML is weak compared with the other established prognostic factors.
• AMLにおけるWT1発現量と染色体・遺伝子異常の関連

  日高 大輔, 小野澤 真弘, 橋口 淳一, 宮下 直洋, 笠原 耕平, 藤澤 真一, 早瀬 英子, 岡田 耕平, 白鳥 聡一, 後藤 秀樹, 杉田 純一, 中川 雅夫, 加畑 馨, 橋本 大吾, 遠藤 知之, 山本 聡, 堤 豊, 長谷山 美仁, 永嶋 貴博, 盛 暁生, 太田 秀一, 酒井 基, 石原 敏道, 今井 陽俊, 宮城島 拓人, 柿木 康孝, 黒澤 光俊, 小林 一, 岩崎 博, 清水 力, 近藤 健, 豊嶋 崇徳

  臨床血液 (一社)日本血液学会-東京事務局 59 (7) 964 - 964 0485-1439 2018/07
• Hematogones Predict Better Outcome in Allogeneic Hematopoietic Stem Cell Transplantation Irrespective of Graft Sources.

  Ishio T, Sugita J, Tateno T, Hidaka D, Hayase E, Shiratori S, Okada K, Goto H, Onozawa M, Nakagawa M, Hashimoto D, Kahata K, Fujimoto K, Endo T, Kondo T, Teshima T

  Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 24 (10) 1990 - 1996 1083-8791 2018/06 [Refereed][Not invited]
  
• Ruxolitinib protects skin stem cells and maintains skin homeostasis in murine graft-versus-host disease

  Shuichiro Takahashi, Daigo Hashimoto, Eiko Hayase, Reiki Ogasawara, Hiroyuki Ohigashi, Takahide Ara, Emi Yokoyama, Ko Ebata, Satomi Matsuoka, Geoffrey R. Hill, Junichi Sugita, Masahiro Onozawa, Takanori Teshima

  Blood 131 (18) 2074 - 2085 1528-0020 2018/05/03 [Refereed][Not invited]
   

  Graft-versus-host disease (GVHD) is the major complication after allogeneic stem cell transplantation (SCT). Emerging evidence indicates that GVHD leads to injury of intestinal stem cells. However, it remains to be investigated whether skin stem cells could be targeted in skin GVHD. Lgr51 hair follicle stem cells (HFSCs) contribute to folliculogenesis and have a multipotent capacity to regenerate all epithelial cells in repair. We studied the fate of Lgr51 HFSCs after SCT and explored the novel treatment to protect Lgr51 HFSCs against GVHD using murine models of SCT. We found that GVHD reduced Lgr51 HFSCs in association with impaired hair regeneration and wound healing in the skin after SCT. Topical corticosteroids, a standard of care for a wide range of skin disorders including GVHD, damaged HFSCs and failed to improve skin homeostasis, despite of their anti-inflammatory effects. In contrast, JAK1/2 inhibitor ruxolitinib significantly ameliorated skin GVHD, protected Lgr51 HFSCs, and restored hair regeneration and wound healing after SCT. We, for the first time, found that GVHD targets Lgr51 HFSCs and that topical ruxolitinib represents a novel strategy to protect skin stem cells and maintain skin homeostasis in GVHD.
• Cecum ulcer is a reliable endoscopic finding in cytomegalovirus colitis concomitant with graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

  Kana Matsuda, Shoko Ono, Marin Ishikawa, Shuichi Miyamoto, Satoshi Abiko, Momoko Tsuda, Keiko Yamamoto, Takahiko Kudo, Yuichi Shimizu, Eiko Hayase, Daigo Hashimoto, Takanori Teshima, Yoshihiro Matsuno, Naoya Sakamoto

  Annals of Hematology 97 (5) 877 - 883 1432-0584 2018/05/01 [Refereed][Not invited]
   

  Although graft-versus-host disease (GVHD) is the major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), cytomegalovirus (CMV) reactivation also occurs in patients after allo-HSCT and these conditions often clinically overlap. The aim of this study was to determine reliable endoscopic findings of CMV colitis in patients with gastrointestinal graft-versus-host-disease (GI-GVHD). Patients after allo-HSCT who were histologically confirmed to have GI-GVHD with or without CMV colitis and patients with an immunosuppressive condition were retrospectively analyzed. We divided the patients into three groups: GI-GVHD with CMV colitis (group A), GI-GVHD without CMV colitis (group B), and CMV colitis without undergoing allo-HSCT (group C). From medical records, the involved colorectal areas and endoscopic findings according to the groups were compared. A total of 70 patients were divided into three groups (group A: n = 19, group B: n = 28, group C: n = 23). Mucosal injuries in groups A and C frequently occurred in the cecum including ileocecal valves. On the other hand, there were no abnormal lesions on ileocecal valves in group B. Furthermore, ulcer lesions were more frequently observed in groups A and C than in group B (p < 0.001). The sensitivity and specificity of mucosal injuries in the cecum for prediction of CMV colitis were 89.5 and 76.5%, respectively, and mucosal injuries in the cecum were more reliable findings than CMV antigenemia. Ulcer lesions in the cecum are reliable endoscopic findings for CMV colitis in patients with GI-GVHD after allo-HSCT.
• A novel heterozygous ITGB3 p.T720del inducing spontaneous activation of integrin αIIbβ3 in autosomal dominant macrothrombocytopenia with aggregation dysfunction

  Naohiro Miyashita, Masahiro Onozawa, Koji Hayasaka, Takahiro Yamada, Ohsuke Migita, Kenichiro Hata, Kohei Okada, Hideki Goto, Masao Nakagawa, Daigo Hashimoto, Kaoru Kahata, Takeshi Kondo, Shinji Kunishima, Takanori Teshima

  Annals of Hematology 97 (4) 629 - 640 1432-0584 2018/04/01 [Refereed][Not invited]
   

  We identified a novel heterozygous ITGB3 p.T720del mutation in a pedigree with macrothrombocytopenia exhibiting aggregation dysfunction. Platelet aggregation induced by ADP and collagen was significantly reduced, while ristocetin aggregation was normal. Integrin αIIbβ3 was partially activated in a resting status, but platelet expression of αIIbβ3 was downregulated. Functional analysis using a cell line showed spontaneous phosphorylation of FAK in αIIb/β3 (p.T720del)-transfected 293T cells in suspension conditions. Abnormal cytoplasmic protrusions, membrane ruffling, and cytoplasmic localization of αIIbβ3 were observed in αIIb/β3 (p.T720del)-transfected CHO cells. Such morphological changes were reversed by treatment with an FAK inhibitor. These findings imply spontaneous, but partial, activation of αIIbβ3 followed by phosphorylation of FAK as the initial mechanism of abnormal thrombopoiesis. Internalization and decreased surface expression of αIIbβ3 would contribute to aggregation dysfunction. We reviewed the literature of congenital macrothrombocytopenia associated with heterozygous ITGA2B or ITGB3 mutations. Reported mutations were highly clustered at the membrane proximal region of αIIbβ3, which affected the critical interaction between αIIb R995 and β3 D723, resulting in a constitutionally active form of the αIIbβ3 complex. Macrothrombocytopenia caused by a heterozygous activating mutation of ITGA2B or ITGB3 at the membrane proximal region forms a distinct entity of rare congenital thrombocytopenia.
• Vitamin A–coupled liposomes containing siRNA against HSP47 ameliorate skin fibrosis in chronic graft-versus-host disease

  Tomohiro Yamakawa, Hiroyuki Ohigashi, Daigo Hashimoto, Eiko Hayase, Shuichiro Takahashi, Miyono Miyazaki, Kenjiro Minomi, Masahiro Onozawa, Yoshiro Niitsu, Takanori Teshima

  Blood 131 (13) 1476 - 1485 1528-0020 2018/03/29 [Refereed][Not invited]
   

  Chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (SCT) is characterized by multiorgan fibrosis and profoundly affects the quality of life of transplant survivors. Heat shock protein 47 (HSP47), a collagen-specific molecular chaperone, plays a critical role in collagen synthesis in myofibroblasts. We explored the role of HSP47 in the fibrotic process of cutaneous chronic GVHD in mice. Immunohistochemical analysis showed massive fibrosis with elevated amounts of collagen deposits and accumulation of F4/801 macrophages, as well as myofibroblasts expressing HSP47 and retinol-binding protein 1 in the skin after allogeneic SCT. Repeated injection of anti–colony-stimulating factor (CSF-1) receptor-blocking antibodies significantly reduced HSP471 myofibroblasts in the skin, indicating a macrophage-dependent accumulation of myofibroblasts. Vitamin A-coupled liposomes carrying HSP47 small interfering RNA (siRNA) (VA-lip HSP47) delivered HSP47 siRNA to cells expressing vitamin A receptors and knocked down their HSP47 in vitro. Intravenously injected VA-lip HSP47 were specifically distributed to skin fibrotic lesions and did not affect collagen synthesis in healthy skin. VA-lip HSP47 knocked down HSP47 expression in myofibroblasts and significantly reduced collagen deposition without inducing systemic immunosuppression. It also abrogated fibrosis in the salivary glands. These results highlight a cascade of fibrosis in chronic GVHD macrophage production of transforming growth factor b mediates fibroblast differentiation to HSP471 myofibroblasts that produce collagen. VA-lip HSP47 represent a novel strategy to modulate fibrosis in chronic GVHD by targeting HSP471 myofibroblasts without inducing immunosuppression.
• T-cell depletion effects of low-dose antithymocyte globulin for GVHD prophylaxis in HLA-matched allogeneic peripheral blood stem cell transplantation.

  Shiratori S, Kosugi-Kanaya M, Hayase E, Okada K, Goto H, Sugita J, Onozawa M, Nakagawa M, Kahata K, Hashimoto D, Endo T, Kondo T, Teshima T

  Transplant immunology 46 21 - 22 0966-3274 2018/02 [Refereed][Not invited]
  
• ADMINISTRATION OF FIBRINOGEN CONCENTRATE REDUCED TRANSFUSION VOLUME IN CADAVERIC LIVER TRANSPLANTATION SURGERY

  Uwatoko Takayo, Goto Ryoichi, Watanabe Chiaki, Akizawa Koji, Shimamura Tsuyoshi, Shimizu Chikara, Teshima Takanori, Hayase Eiko, Kahata Kaoru, Hashimoto Daigo, Ito Makoto, Uozumi Ryo, Hayashi Yasuhiro, Sugita Junichi, Koshizuka Yasuyuki

  Japanese Journal of Transfusion and Cell Therapy 一般社団法人 日本輸血・細胞治療学会 64 (5) 641 - 648 1881-3011 2018 [Not refereed][Not invited]
   

  <p><b>Background:</b> Liver transplantation is associated with massive bleeding and transfusion in recipients with coagulopathy. A previous study reported that intraoperative fibrinogen concentrate (IOFC) reduces transfusion volume in liver transplant procedures. In our institute, IOFC was introduced in 2012 for preventing massive bleeding in cadaveric liver transplantation. We studied the effects of IOFC on the amount of bleeding and transfusion during surgery.</p><p><b>Patients andMethods:</b> We retrospectively analyzed 44 adult patients who underwent cadaveric liver transplantation between February 2001 and August 2016. The amount of intraoperative bleeding and transfusion in 25 transplantations that did not use IOFC was compared to that in 19 cases that used IOFC. We also analyzed 33 patients who bled more than their circulating blood volume (16 cases without IOFC, 17 cases with IOFC).</p><p><b>Results:</b> The amount of intraoperative bleeding and transfusion was not significantly different between the two groups. In sub-analysis of 33 patients who bled more than their circulating blood volume, the amount of intraoperative bleeding was significantly reduced in the group that used IOFC. Further, the amount of intraoperative PC transfusion was significantly reduced and the amount of red blood cells and fresh frozen plasma tended to be lower.</p><p><b>Conclusion:</b> Use of IOFC reduced intraoperative massive hemorrhage and PC requirements in cadaveric liver transplantation.</p>
• R-Spondin1 expands Paneth cells and prevents dysbiosis induced by graft-versus-host disease

  Eiko Hayase, Daigo Hashimoto, Kiminori Nakamura, Clara Noizat, Reiki Ogasawara, Shuichiro Takahashi, Hiroyuki Ohigashi, Yuki Yokoi, Rina Sugimoto, Satomi Matsuoka, Takahide Ara, Emi Yokoyama, Tomohiro Yamakawa, Ko Ebata, Takeshi Kondo, Rina Hiramine, Tomoyasu Aizawa, Yoshitoshi Ogura, Tetsuya Hayashi, Hiroshi Mori, Ken Kurokawa, Kazuma Tomizuka, Tokiyoshi Ayabe, Takanori Teshima

  JOURNAL OF EXPERIMENTAL MEDICINE 214 (12) 3507 - 3518 0022-1007 2017/12 [Refereed][Not invited]
   

  The intestinal microbial ecosystem is actively regulated by Paneth cell-derived antimicrobial peptides such as alpha-defensins. Various disorders, including graft-versus-host disease (GVHD), disrupt Paneth cell functions, resulting in unfavorably altered intestinal microbiota (dysbiosis), which further accelerates the underlying diseases. Current strategies to restore the gut ecosystem are bacteriotherapy such as fecal microbiota transplantation and probiotics, and no physiological approach has been developed so far. In this study, we demonstrate a novel approach to restore gut microbial ecology by Wnt agonist R-Spondin1 (R-Spo1) or recombinant a-defensin in mice. R-Spo1 stimulates intestinal stem cells to differentiate to Paneth cells and enhances luminal secretion of a-defensins. Administration of R-Spo1 or recombinant a-defensin prevents GVHD-mediated dysbiosis, thus representing a novel and physiological approach at modifying the gut ecosystem to restore intestinal homeostasis and host-microbiota cross talk toward therapeutic benefits.
• 同種造血幹細胞移植を施行したCSF3R T613I変異陽性非定型慢性骨髄性白血病

  原田 晋平, 岡田 耕平, 日高 大輔, 早瀬 英子, 後藤 秀樹, 橋本 大吾, 加畑 馨, 遠藤 知之, 豊嶋 崇徳

  臨床血液 (一社)日本血液学会-東京事務局 58 (11) 2299 - 2299 0485-1439 2017/11
• Disseminated toxoplasmosis after hematopoietic stem cell transplantation showing unusual magnetic resonance images

  Takahiro Tateno, Masahiro Onozawa, Junichi Hashiguchi, Takashi Ishio, Sayaka Yuzawa, Satomi Matsuoka, Mizuha Kosugi-Kanaya, Kohei Okada, Souichi Shiratori, Hideki Goto, Taichi Kimura, Junichi Sugita, Masao Nakagawa, Daigo Hashimoto, Kaoru Kahata, Katsuya Fujimoto, Tomoyuki Endo, Takeshi Kondo, Shinya Tanaka, Satoshi Hashino, Takanori Teshima

  TRANSPLANT INFECTIOUS DISEASE 19 (4) 1398-2273 2017/08 [Refereed][Not invited]
   

  We herein report a patient who had disseminated toxoplasmosis after hematopoietic stem cell transplantation showing atypical clinical presentation and neuroimaging. Parkinsonism symptoms such as muscle rigidity, bradykinesia, tremor, and postural instability were initial manifestations. Magnetic resonance imaging showed diffuse symmetrical lesions of bilateral basal ganglia lacking ringed enhancement. Post-mortem analysis revealed multiple tachyzoites of Toxoplasma gondii in the basal ganglia, mid brain, cerebellum, and cardiac muscle.
• Diffuse large B-cell lymphoma with a bulky mass in the cranial vault

  Minoru Kanaya, Tomoyuki Endo, Daigo Hashimoto, Shogo Endo, Ryo Takemura, Kohei Okada, Kanako C. Hatanaka, Yoshihiro Matsuno, Takanori Teshima

  INTERNATIONAL JOURNAL OF HEMATOLOGY 106 (2) 147 - 148 0925-5710 2017/08 [Not refereed][Not invited]
  
• Risk factors of human herpesvirus 6 encephalitis/myelitis after allogeneic hematopoietic stem cell transplantation

  Naohiro Miyashita, Tomoyuki Endo, Masahiro Onozawa, Daigo Hashimoto, Takeshi Kondo, Katsuya Fujimoto, Kaoru Kahata, Junichi Sugita, Hideki Goto, Toshihiro Matsukawa, Satoshi Hashino, Takanori Teshima

  TRANSPLANT INFECTIOUS DISEASE 19 (3) 1398-2273 2017/06 [Not refereed][Not invited]
   

  Background: Human herpesvirus 6 (HHV-6) encephalitis/myelitis is now a well-known complication after allogeneic stem cell transplantation (allo-HSCT), particularly after cord blood transplantation (CBT). In this study, we evaluated the risk factors of HHV-6 encephalitis/myelitis. Methods: We evaluated 253 patients who received allo-HSCT from 2007 to 2015 at our institute. HHV-6 encephalitis/myelitis was defined as HHV-6 DNA detection in the cerebrospinal fluid or peripheral blood by polymerase chain reaction in the presence of typical manifestations without other concurrent condition that led to the manifestations. Results: HHV-6 encephalitis/myelitis occurred in 11 patients (4.5%) (9 encephalitis, 3.7%; 2 myelitis, 0.8%). Multivariate analysis showed that CBT, mycophenolate mofetil (MMF) for graft-versus-host disease prophylaxis, history of allogeneic hematopoietic stem cell transplantation (allo-HSCT), and engraftment syndrome (ES) were significantly associated with incidence of HHV-6 encephalitis/myelitis (P=.025, P=.017, P=.017, and P=.014, respectively). Conclusion: Although it has been shown that CBT, ES, and history of allo-HSCT are risk factors for HHV-6 encephalitis/myelitis, our study demonstrated MMF is also a risk factor for the disease.
• MALDI-TOF MS in post-transplant bloodstream infections: reliable identification of causative bacteria in the neutropenic phase

  M. Kanaya, Y. Hayashi, D. Hashimoto, T. Endo, J. Sugita, H. Ohigashi, J. Hashiguchi, T. Matsukawa, S. Matsuoka, M. Kosugi-Kanaya, H. Goto, M. Onozawa, K. Kahata, K. Fujimoto, T. Kondo, K. Akizawa, H. Shibuya, C. Shimizu, T. Teshima

  BONE MARROW TRANSPLANTATION 52 (5) 778 - 780 0268-3369 2017/05 [Not refereed][Not invited]
  
• Graft-versus-host disease targets ovary and causes female infertility in mice

  Sonoko Shimoji, Daigo Hashimoto, Hidetsugu Tsujigiwa, Kohta Miyawaki, Koji Kato, Shuichiro Takahashi, Reiki Ogasawara, Takashi Jiromaru, Hiromi Iwasaki, Toshihiro Miyamoto, Koichi Akashi, Takanori Teshima

  BLOOD 129 (9) 1216 - 1225 0006-4971 2017/03 [Not refereed][Not invited]
   

  Infertility associated with ovarian failure is a serious late complication for female survivors of allogeneic hematopoietic stem cell transplantation (SCT). Although pretransplant conditioning regimen has been appreciated as a cause of ovarian failure, increased application of reduced-intensity conditioning allowed us to revisit other factors possibly affecting ovarian function after allogeneic SCT. We have addressed whether donor T-cell-mediated graft-versus-host disease (GVHD) could be causally related to female infertility in mice. Histological evaluation of the ovaries after SCT demonstrated donor T-cell infiltration in close proximity to apoptotic granulosa cells in the ovarian follicles, resulting in impaired follicular hormone production and maturation of ovarian follicles. Mating experiments showed that female recipients of allogeneic SCT deliver significantly fewer newborns than recipients of syngeneic SCT. GVHD-mediated ovary insufficiency and infertility were independent of conditioning. Pharmacologic GVHD prophylaxis protected the ovary from GVHD and preserved fertility. These results demonstrate for the first time that GVHD targets the ovary and impairs ovarian function and fertility and has important clinical implications in young female transplant recipients with nonmalignant diseases, in whom minimally toxic regimens are used. (Blood. 2017; 129(9): 1216-1225)
• Leukemogenic kinase FIP1L1-PDGFRA and a small ubiquitin-like modifier E3 ligase, PIAS1, form a positive cross-talk through their enzymatic activities

  Makoto Ibata, Junko Iwasaki, Yoichiro Fujioka, Koji Nakagawa, Stephanie Darmanin, Masahiro Onozawa, Daigo Hashimoto, Yusuke Ohba, Shigetsugu Hatakeyama, Takanori Teshima, Takeshi Kondo

  CANCER SCIENCE 108 (2) 200 - 207 1347-9032 2017/02 [Not refereed][Not invited]
   

  Fusion tyrosine kinases play a crucial role in the development of hematological malignancies. FIP1L1-PDGFRA is a leukemogenic fusion kinase that causes chronic eosinophilic leukemia. As a constitutively active kinase, FIP1L1-PDGFRA stimulates downstream signaling molecules, leading to cellular proliferation and the generation of an anti-apoptotic state. Contribution of the N-terminal FIP1L1 portion is necessary for FIP1L1-PDGFRA to exert its full transforming activity, but the underlying mechanisms have not been fully characterized. We identified PIAS1 as a FIP1L1-PDGFRA association molecule by yeast two-hybrid screening. Our analyses indicate that the FIP1L1 portion of FIP1L1-PDGFRA is required for efficient association with PIAS1. As a consequence of the association, FIP1L1-PDGFRA phosphorylates PIAS1. Moreover, the kinase activity of FIP1L1-PDGFRA stabilizes PIAS1. Therefore, PIAS1 is one of the downstream targets of FIP1L1-PDGFRA. Moreover, we found that PIAS1, as a SUMO E3 ligase, sumoylates and stabilizes FIP1L1-PDGFRA. In addition, suppression of PIAS1 activity by a knockdown experiment resulted in destabilization of FIP1L1-PDGFRA. Therefore, FIP1L1-PDGFRA and PIAS1 form a positive cross-talk through their enzymatic activities. Suppression of sumoylation by ginkgolic acid, a small molecule compound inhibiting a SUMO E1-activating enzyme, also destabilizes FIP1L1-PDGFRA, and while the tyrosine kinase inhibitor imatinib suppresses FIP1L1-PDGFRA-dependent cell growth, ginkgolic acid or siRNA of PIAS1 has a synergistic effect with imatinib. In conclusion, our results suggest that sumoylation by PIAS1 is a potential target in the treatment of FIP1L1-PDGFRA-positive chronic eosinophilic leukemia.
• Graft-versus-host disease in the ovary potentially causes female infertility after allogeneic hematopoietic stem cell transplantation.

  Shimoji S, Hashimoto D, Teshima T

  [Rinsho ketsueki] The Japanese journal of clinical hematology 58 (7) 827 - 834 0485-1439 2017 [Refereed][Not invited]
  
• Reduced-dose methotrexate in combination with tacrolimus was associated with rapid engraftment and recovery from oral mucositis without affecting the incidence of GVHD

  Toshihiro Matsukawa, Daigo Hashimoto, Junichi Sugita, Seitarou Nakazawa, Takae Matsushita, Haruhiko Kashiwazaki, Hideki Goto, Masahiro Onozawa, Kaoru Kahata, Katsuya Fujimoto, Tomoyuki Endo, Takeshi Kondo, Satoshi Hashino, Yutaka Yamazaki, Takanori Teshima

  INTERNATIONAL JOURNAL OF HEMATOLOGY 104 (1) 117 - 124 0925-5710 2016/07 [Not refereed][Not invited]
   

  Allogeneic hematopoietic stem cell transplantation is a curable treatment for hematological diseases. Graft-versus-host disease (GVHD) causes morbidity and mortality after HSCT. Methotrexate (MTX) is used for GVHD prophylaxis, but its appropriate dose remains unclear. In the present study, we compared the efficacy and toxicity of 15-10-10 MTX (day +1: 15 mg/m(2); days +3 and +6: 10 mg/m(2)) with 10-7-7 MTX (day +1: 10 mg/m(2); day +3 and +6: 7 mg/m(2)) in combination with tacrolimus. The cumulative incidence rates of grades II-IV acute GVHD, grades III-IV acute GVHD and chronic GVHD in the 15-10-10 MTX and 10-7-7 MTX groups did not differ to a statistically significant extent. The median time for neutrophil engraftment in the 15-10-10 MTX group was 16 days (range, 11-31 days), while that in the 10-7-7 group was 15 days (range, 12-19 days) (P = 0.024). Moreover, the median time for platelet recovery was significantly shorter in the 10-7-7 MTX group (22 days; range, 13-49 days) than that in the 15-10-10 MTX group (27 days; range, 9-405 days) (P = 0.027). The duration of oral mucositis was significantly shorter in the patients who received a reduced dose of MTX (median, 4.5 vs 13.0 days; P = 0.013). In conclusion, GVHD prophylaxis with a reduced dose of MTX was associated with earlier engraftment and earlier recovery from mucositis in comparison to a standard dose of MTX, without affecting the incidence of GVHD.
• The Mononuclear Phagocyte System in Organ Transplantation

  J. Ochando, W. -H. Kwan, F. Ginhoux, J. A. Hutchinson, D. Hashimoto, M. Collin

  AMERICAN JOURNAL OF TRANSPLANTATION 16 (4) 1053 - 1069 1600-6135 2016/04 [Not refereed][Not invited]
   

  The mononuclear phagocyte system (MPS) comprises monocytes, macrophages and dendritic cells (DCs). Over the past few decades, classification of the cells of the MPS has generated considerable controversy. Recent studies into the origin, developmental requirements and function of MPS cells are beginning to solve this problem in an objective manner. Using high-resolution genetic analyses and fate-mapping studies, three main mononuclear phagocyte lineages have been defined, namely, macrophage populations established during embryogenesis, monocyte-derived cells that develop during adult life and DCs. These subsets and their diverse subsets have specialized functions that are largely conserved between species, justifying the introduction of a new, universal scheme of nomenclature and providing the framework for therapeutic manipulation of immune responses in the clinic. In this review, we have commented on the implications of this novel MPS classification in solid organ transplantation. The authors review the implications of a novel mononuclear phagocyte system nomenclature in solid organ transplantation and provide the phenotypic characterization to distinguish its multiple subsets.
• Expansion and Activation of CD103(+) Dendritic Cell Progenitors at the Tumor Site Enhances Tumor Responses to Therapeutic PD-L1 and BRAF Inhibition

  Helene Salmon, Juliana Idoyaga, Adeeb Rahman, Marylene Leboeuf, Romain Remark, Stefan Jordan, Maria Casanova-Acebes, Makhzuna Khudoynazarova, Judith Agudo, Navpreet Tung, Svetoslav Chakarov, Christina Rivera, Brandon Hogstad, Marcus Bosenberg, Daigo Hashimoto, Sacha Gnjatic, Nina Bhardwaj, Anna Karolina Palucka, Brian D. Brown, Joshua Brody, Florent Ginhoux, Miriam Merad

  IMMUNITY 44 (4) 924 - 938 1074-7613 2016/04 [Not refereed][Not invited]
   

  Large numbers of melanoma lesions develop resistance to targeted inhibition of mutant BRAF or fail to respond to checkpoint blockade. We explored whether modulation of intratumoral antigen-presenting cells (APCs) could increase responses to these therapies. Using mouse melanoma models, we found that CD103(+) dendritic cells (DCs) were the only APCs transporting intact antigens to the lymph nodes and priming tumor-specific CD8(+) T cells. CD103(+) DCs were required to promote anti-tumoral effects upon blockade of the checkpoint ligand PD-L1; however, PD-L1 inhibition only led to partial responses. Systemic administration of the growth factor FLT3L followed by intratumoral poly I:C injections expanded and activated CD103(+) DC progenitors in the tumor, enhancing responses to BRAF and PD-L1 blockade and protecting mice from tumor rechallenge. Thus, the paucity of activated CD103(+) DCs in tumors limits checkpoint-blockade efficacy and combined FLT3L and poly I:C therapy can enhance tumor responses to checkpoint and BRAF blockade.
• Allogeneic hematopoietic stem cell transplantation following reduced-intensity conditioning for mycosis fungoides and Sezary syndrome

  Souichi Shiratori, Katsuya Fujimoto, Machiko Nishimura, Kanako C. Hatanaka, Mizuha Kosugi-Kanaya, Kohei Okada, Junichi Sugita, Akio Shigematsu, Daigo Hashimoto, Tomoyuki Endo, Takeshi Kondo, Riichiro Abe, Satoshi Hashino, Yoshihiro Matsuno, Hiroshi Shimizu, Takanori Teshima

  HEMATOLOGICAL ONCOLOGY 34 (1) 9 - 16 0278-0232 2016/03 [Not refereed][Not invited]
   

  Advanced-stage mycosis fungoides and Sezary syndrome (MF/SS) have a poor prognosis. Allogeneic hematopoietic stem cell transplantation (HSCT), particularly using a reduced-intensity conditioning (RIC) regimen, is a promising treatment for advanced-stage MF/SS. We performed RIC-HSCT in nine patients with advanced MF/SS. With a median follow-up period of 954days after HSCT, the estimated 3-year overall survival was 85.7% (95% confidence interval, 33.4-97.9%) with no non-relapse mortality. Five patients relapsed after RIC-HSCT; however, in four patients whose relapse was detected only from the skin, persistent complete response was achieved in one patient, and the disease was manageable in other three patients by the tapering of immunosuppressants and donor lymphocyte infusion, suggesting that graft-versus-lymphoma effect and down-staging' effect from advanced stage to early stage by HSCT improve the prognosis of advanced-stage MF/SS. These results suggest that RIC-HSCT is an effective treatment for advanced MF/SS. Copyright (c) 2014 John Wiley & Sons, Ltd.
• Cytogenetically Unrelated Clones in Acute Myeloid Leukemia Showing Different Responses to Chemotherapy

  Kohei Kasahara, Masahiro Onozawa, Naohiro Miyashita, Emi Yokohata, Miho Yoshida, Minoru Kanaya, Mizuha Kosugi-Kanaya, Ryo Takemura, Shojiro Takahashi, Junichi Sugita, Akio Shigematsu, Mutsumi Takahata, Shinichi Fujisawa, Daigo Hashimoto, Katsuya Fujimoto, Tomoyuki Endo, Takeshi Kondo, Takanori Teshima

  Case Reports in Hematology 2016 1 - 5 2090-6560 2016 [Refereed][Not invited]
   

  We report a case of acute myeloid leukemia (AML) with two cytogenetically unrelated clones. The patient was a 45-year-old male who was diagnosed with acute monoblastic leukemia (AMoL). Initial G-band analysis showed 51,XY,+6,+8,inv(9)(p12q13)c,+11,+13,+19[12]/52,idem,+Y[8], but G-band analysis after induction therapy showed 45,XY,-7,inv(9)(p12q13)c[19]/46,XY,inv(9)(p12q13)c[1]. Retrospective FISH analysis revealed a cryptic monosomy 7 clone in the initial AML sample. The clone with multiple trisomies was eliminated after induction therapy and never recurred, but a clone with monosomy 7 was still detected in myelodysplastic marrow with a normal blast percentage. Both clones were successfully eliminated after related peripheral blood stem cell transplantation, but the patient died of relapsed AML with monosomy 7. We concluded that one clone was de novo AMoL with chromosome 6, 8, 11, 13, and 19 trisomy and that the other was acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) with chromosome 7 monosomy showing different responses to chemotherapy. Simultaneous onset of cytogenetically unrelated hematological malignancies that each have a different disease status is a rare phenomenon but is important to diagnose for a correct understanding of the disease status and for establishing an appropriate treatment strategy.
• Decreased secretion of Paneth cell -defensins in graft-versus-host disease

  Y. Eriguchi, K. Nakamura, D. Hashimoto, S. Shimoda, N. Shimono, K. Akashi, T. Ayabe, T. Teshima

  TRANSPLANT INFECTIOUS DISEASE 17 (5) 702 - 706 1398-2273 2015/10 [Not refereed][Not invited]
   

  BackgroundIntestinal microbial ecology is actively regulated by Paneth cell-derived antimicrobial peptides, -defensins. Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (SCT). We previously demonstrated that Paneth cells are targeted by GVHD, and their expression of antimicrobial peptide -defensins is impaired, leading to a loss of physiological diversity among the microflora and development of bloodstream infection. Herein, we evaluated whether fecal levels of -defensins could be surrogate marker of intestinal dysbiosis. MethodsWe directly measured -defensin cryptdin-1 (Crp1) in fecal pellets of mice with GVHD by using a novel enzyme-linked immunosorbent assay. ResultsFecal levels of Crp1 were significantly decreased in mice with GVHD but unchanged in mice without GVHD after SCT. These were correlated with intestinal flora diversity. ConclusionWe demonstrate a link between reduced secretion of Paneth cell -defensins and dysbiosis of intestinal flora in GVHD. Fecal levels of -defensins could be surrogate markers for intestinal microbial homeostasis.
• Key players in intestinal GVHD

  Daigo Hashimoto, Takanori Teshima

  [Rinshō ketsueki] The Japanese journal of clinical hematology 56 807 - 814 0485-1439 2015/07/01 [Not refereed][Not invited]
   

  Acute graft versus host disease (GVHD) is a potentially life threatening complication after allogeneic hematopoietic stem cell transplantation. The gut is one of the most frequently affected organs in GVHD. Intestinal GVHD is often resistant to current therapies for GVHD and greatly affects the nutritional status of patients. Recent advances in understanding the biology of the intestinal immune system have revealed the significance of mechanical and chemical barriers involving the intestinal mucosa and intestinal microflora in the pathophysiology of GVHD. These barriers and flora are tightly regulated by key populations such as intestinal stem cells, Paneth cells, innate lymphoid cells, and macrophages. Recent findings for these key players in the process of intestinal GVHD are reviewed in this article.
• alpha-Mannan induces Th17-mediated pulmonary graft-versus-host disease in mice

  Hidetaka Uryu, Daigo Hashimoto, Koji Kato, Eiko Hayase, Satomi Matsuoka, Reiki Ogasawara, Shuichiro Takahashi, Yoshinobu Maeda, Hiromi Iwasaki, Toshihiro Miyamoto, Shinobu Saijo, Yoichiro Iwakura, Geoffrey R. Hill, Koichi Akashi, Takanori Teshima

  BLOOD 125 (19) 3014 - 3023 0006-4971 2015/05 [Not refereed][Not invited]
   

  Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapy for various hematopoietic disorders. Graft-versus-host disease (GVHD) and infections are the major obstacles of HSCT, and their close relationship has been suggested. Although roles of bacterial and viral infections in the pathophysiology of GVHD are well described, impacts of fungal infection on GVHD remain to be elucidated. In mouse models of GVHD, injection of a-mannan (Mn), a major component of fungal cell wall, or heat-killed Candida albicans exacerbated GVHD, particularly in the lung. Mn-induced donor T-cell polarization toward Th17 and lung-specific chemokine environment in GVHD led to accumulation of Th17 cells in the lung. The detrimental effects of Mn on GVHD depended on donor IL-17A production and host C-type lectin receptor Dectin-2. These results suggest a previously unrecognized link between pulmonary GVHD and fungal infection after allogeneic HSCT.
• Requirement for Innate Immunity and CD90(+)NK1.1(-) Lymphocytes to Treat Established Melanoma with Chemo-Immunotherapy

  Marina Moskalenko, Michael Pan, Yichun Fu, Ellen H. de Moll, Daigo Hashimoto, Arthur Mortha, Marylene Leboeuf, Padmini Jayaraman, Sebastian Bernardo, Andrew G. Sikora, Jedd Wolchok, Nina Bhardwaj, Miriam Merad, Yvonne Saenger

  CANCER IMMUNOLOGY RESEARCH 3 (3) 296 - 304 2326-6066 2015/03 [Not refereed][Not invited]
   

  We sought to define cellular immune mechanisms of synergy between tumor-antigen-targeted monoclonal antibodies and chemotherapy. Established B16 melanoma in mice was treated with cytotoxic doses of cyclophosphamide in combination with an antibody targeting tyrosinase-related protein 1 (alpha TRP1), a native melanoma differentiation antigen. We find that Fc gamma receptors are required for efficacy, showing that antitumor activity of combination therapy is immune mediated. Rag1(-/-) mice deficient in adaptive immunity are able to clear tumors, and thus innate immunity is sufficient for efficacy. Furthermore, previously treated wild-type mice are not significantly protected against tumor reinduction, as compared with mice inoculated with irradiated B16 alone, consistent with a primarily innate immune mechanism of action of chemo-immunotherapy. In contrast, mice deficient in both classical natural killer (NK) lymphocytes and nonclassical innate lymphocytes (ILC) due to deletion of the IL2 receptor common gamma chain IL2 gamma c(-/-)) are refractory to chemo-immunotherapy. Classical NK lymphocytes are not critical for treatment, as depletion of NK1.1(+) cells does not impair antitumor effect. Depletion of CD90(+)NK1.1(-) lymphocytes, however, both diminishes therapeutic benefit and decreases accumulation of macrophages within the tumor. Tumor clearance during combination chemo-immunotherapy with monoclonal antibodies against native antigen is mediated by the innate immune system. We highlight a novel potential role for CD90(+)NK1.1(-) ILCs in chemo-immunotherapy. (C) 2015 AACR.
• FIP1L1 presence in FIP1L1-RARA or FIP1L1-PDGFRA differentially contributes to the pathogenesis of distinct types of leukemia

  Junko Iwasaki, Takeshi Kondo, Stephanie Darmanin, Makoto Ibata, Masahiro Onozawa, Daigo Hashimoto, Naoya Sakamoto, Takanori Teshima

  ANNALS OF HEMATOLOGY 93 (9) 1473 - 1481 0939-5555 2014/09 [Refereed][Not invited]
   

  FIP1-like 1 (FIP1L1) is associated with two leukemogenic fusion genes: FIP1L1-retinoic acid receptor alpha (RARA) and FIP1L1-platelet-derived growth factor receptor alpha (PDGFRA). Analyses of a series of deletion mutants revealed that the FIP1 motif in FIP1L1-RARA plays a pivotal role in its homodimerization and transcriptional repressor activity. However, in FIP1L1-PDGFRA, the C-terminal PDGFRA portion possesses the ability of forming a homodimer by itself, making FIP1L1 dispensable for constitutive activation of this kinase. Both the full-length and the C-terminal PDGFRA portion of FIP1L1-PDGFRA could transform the IL-3-dependent hematopoietic cell line, BAF-B03. Moreover, when either the full-length or the C-terminal PDGFRA portion of FIP1L1-PDGFRA was introduced in these cells, they grew in the absence of IL-3. The cells having the C-terminal PDGFRA portion of FIP1L1-PDGFRA, however, were partially IL-3 dependent, whereas the cells having the full-length FIP1L1-PDGFRA became completely IL-3 independent for their growth. Taken together, these results show that FIP1L1 differentially contributes to the pathogenesis of distinct types of leukemia.
• Erratum: Crosstalk between muscularis macrophages and enteric neurons regulates gastrointestinal motility (Cell (2014) 158 (300â€"313) )

  Paul Andrew Muller, Balázs Koscsó, Gaurav Manohar Rajani, Korey Stevanovic, Marie Luise Berres, Daigo Hashimoto, Arthur Mortha, Marylene Leboeuf, Xiu Min Li, Daniel Mucida, E. Richard Stanley, Stephanie Dahan, Kara Gross Margolis, Michael David Gershon, Miriam Merad, Milena Bogunovic

  Cell 158 1210  0092-8674 2014/08/28 [Not refereed][Not invited]
  
• Crosstalk between Muscularis Macrophages and Enteric Neurons Regulates Gastrointestinal Motility

  Paul Andrew Muller, Balazs Koscso, Gaurav Manohar Rajani, Korey Stevanovic, Marie-Luise Berres, Daigo Hashimoto, Arthur Mortha, Marylene Leboeuf, Xiu-Min Li, Daniel Mucida, E. Richard Stanley, Stephanie Dahan, Kara Gross Margolis, Michael David Gershon, Miriam Merad, Milena Bogunovic

  CELL 158 (2) 300 - 313 0092-8674 2014/07 [Not refereed][Not invited]
   

  Intestinal peristalsis is a dynamic physiologic process influenced by dietary and microbial changes. It is tightly regulated by complex cellular interactions; however, our understanding of these controls is incomplete. A distinct population of macrophages is distributed in the intestinal muscularis externa. We demonstrate that, in the steady state, muscularis macrophages regulate peristaltic activity of the colon. They change the pattern of smooth muscle contractions by secreting bone morphogenetic protein 2 (BMP2), which activates BMP receptor (BMPR) expressed by enteric neurons. Enteric neurons, in turn, secrete colony stimulatory factor 1 (CSF1), a growth factor required for macrophage development. Finally, stimuli from microbial commensals regulate BMP2 expression by macrophages and CSF1 expression by enteric neurons. Our findings identify a plastic, microbiotadriven crosstalk between muscularis macrophages and enteric neurons that controls gastrointestinal motility.
• Stenotrophomonas maltophilia infection during allogeneic hematopoietic stem cell transplantation: a single-center experience

  Souichi Shiratori, Kentaro Wakasa, Kohei Okada, Junichi Sugita, Koji Akizawa, Akio Shigematsu, Daigo Hashimoto, Katsuya Fujimoto, Tomoyuki Endo, Takeshi Kondo, Chikara Shimizu, Satoshi Hashino, Takanori Teshima

  CLINICAL TRANSPLANTATION 28 (6) 656 - 661 0902-0063 2014/06 [Refereed][Not invited]
   

  To examine risk factors for Stenotrophomonas maltophilia (S.maltophilia) infection during allogeneic hematopoietic stem cell transplantation (allo-HSCT), we retrospectively analyzed 259 patients who underwent allo-HSCT. Not only S.maltophilia infection but also S.maltophilia colonization was associated with mortality during allo-HSCT. Among 52 episodes in 39 patients in whom S.maltophilia was detected, documented infection developed in 33 episodes (25 patients). The onset of S.maltophilia infection in the period from the conditioning regimen to engraftment was associated with a high mortality rate. Breakthrough S.maltophilia infection developed in 24% of the patients during prophylactic administration of fluoroquinolones, to which S.maltophilia is sensitive. Reinsertion of a central venous catheter (CVC) immediately after removal was suggested to be a risk for persistent S.maltophilia infection in the period of neutropenia. Our results indicated that (i) onset of S.maltophilia infection in the period from the conditioning therapy to engraftment and (ii) removal and immediate reinsertion of a CVC as treatment after the onset of S.maltophilia infection are possible risk factors for S.maltophilia-related mortality during allo-HSCT.
• Bone Marrow Graft-versus-Host Disease: Evaluation of Its Clinical Impact on Disrupted Hematopoiesis after Allogeneic Hematopoietic Stem Cell Transplantation

  Yusuke Shono, Souichi Shiratori, Mizuha Kosugi-Kanaya, Satoshi Ueha, Junichi Sugita, Akio Shigematsu, Takeshi Kondo, Daigo Hashimoto, Katsuya Fujimoto, Tomoyuki Endo, Mitsufumi Nishio, Satoshi Hashino, Yoshihiro Matsuno, Kouji Matsushima, Junji Tanaka, Masahiro Imamura, Takanori Teshima

  BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION 20 (4) 495 - 500 1083-8791 2014/04 [Refereed][Not invited]
   

  Idiopathic cytopenias are frequently observed in patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We have previously reported the effect of graft-versus-host disease (GVHD) on bone marrow (BM) in murine models, indicating that the osteoblast injury mediated by donor T cells was associated with bone marrow suppression and delayed immune reconstitution. In this study, we prospectively evaluated the relevance of these findings in 51 patients. Patients with chronic GVHD manifested the loss of osteoblasts, contributing to cytopenic symptoms (P =.0427 compared with patients without cytopenic symptoms). The loss of osteoblasts was significantly associated with the extensive type of chronic GVHD (P =.012), and flow cytometric analyses revealed lower numbers of CD19(+) B cells and a significantly increased CD4 to CD8 ratio (P.0002) in these patients. Our data, for the first time to our knowledge, summarize the detailed analyses of the effect of GVHD on BM in the clinical allo-HSCT patients. (c) 2014 American Society for Blood and Marrow Transplantation.
• Central Role of Conventional Dendritic Cells in Regulation of Bone Marrow Release and Survival of Neutrophils

  Jingjing Jiao, Ana-Cristina Dragomir, Peri Kocabayoglu, Adeeb H. Rahman, Andrew Chow, Daigo Hashimoto, Marylene Leboeuf, Thomas Kraus, Thomas Moran, Gonzalo Carrasco-Avino, Scott L. Friedman, Miriam Merad, Costica Aloman

  JOURNAL OF IMMUNOLOGY 192 (7) 3374 - 3382 0022-1767 2014/04 [Refereed][Not invited]
   

  Neutrophils are the most abundant cell type in the immune system and play an important role in the innate immune response. Using a diverse range of mouse models with either defective dendritic cell ( DC) development or conditional DC depletion, we provide in vivo evidence indicating that conventional DCs play an important role in the regulation of neutrophil homeostasis. Flk2, Flt3L, and Batf3 knockout mice, which have defects in DC development, have increased numbers of liver neutrophils in the steady state. Conversely, neutrophil frequency is reduced in DC-specific PTEN knockout mice, which have an expansion of CD8(+) and CD103(+) DCs. In chimeric CD11c-DTR mice, conventional DC depletion results in a systemic increase of neutrophils in peripheral organs in the absence of histological inflammation or an increase in proinflammatory cytokines. This effect is also present in splenectomized chimeric CD11c-DTR mice and is absent in chimeric mice with 50% normal bone marrow. In chimeric CD11c-DTR mice, diphtheria toxin treatment results in enhanced neutrophil trafficking from the bone marrow into circulation and increased neutrophil recruitment. Moreover, there is an increased expression of chemokines/cytokines involved in neutrophil homeostasis and reduced neutrophil apoptosis. These data underscore the role of the DC pool in regulating the neutrophil compartment in nonlymphoid organs.
• Interplay of host microbiota, genetic perturbations, and inflammation promotes local development of intestinal neoplasms in mice

  Gerold Bongers, Michelle E. Pacer, Thais H. Geraldino, Lili Chen, Zhengxiang He, Daigo Hashimoto, Glaucia C. Furtado, Jordi Ochando, Kevin A. Kelley, Jose C. Clemente, Miriam Merad, Harm van Bakel, Sergio A. Lira

  JOURNAL OF EXPERIMENTAL MEDICINE 211 (3) 457 - 472 0022-1007 2014/03 [Refereed][Not invited]
   

  The preferential localization of some neoplasms, such as serrated polyps (SPs), in specific areas of the intestine suggests that nongenetic factors may be important for their development. To test this hypothesis, we took advantage of transgenic mice that expressed HB- EGF throughout the intestine but developed SPs only in the cecum. Here we show that a hostspecific microbiome was associated with SPs and that alterations of the microbiota induced by antibiotic treatment or by embryo transfer rederivation markedly inhibited the formation of SPs in the cecum. Mechanistically, development of SPs was associated with a local decrease in epithelial barrier function, bacterial invasion, production of antimicrobials, and increased expression of several inflammatory factors such as IL-17, Cxcl2, Tnf-alpha, and IL-1. Increased numbers of neutrophils were found within the SPs, and their depletion significantly reduced polyp growth. Together these results indicate that nongenetic factors contribute to the development of SPs and suggest that the development of these intestinal neoplasms in the cecum is driven by the interplay between genetic changes in the host, an inflammatory response, and a host-specific microbiota.
• Microbiota-Dependent Crosstalk Between Macrophages and ILC3 Promotes Intestinal Homeostasis

  Arthur Mortha, Aleksey Chudnovskiy, Daigo Hashimoto, Milena Bogunovic, Sean P. Spencer, Yasmine Belkaid, Miriam Merad

  SCIENCE 343 (6178) 1477 - + 0036-8075 2014/03 [Refereed][Not invited]
   

  The intestinal microbiota and tissue-resident myeloid cells promote immune responses that maintain intestinal homeostasis in the host. However, the cellular cues that translate microbial signals into intestinal homeostasis remain unclear. Here, we show that deficient granulocyte-macrophage colony-stimulating factor (GM-CSF) production altered mononuclear phagocyte effector functions and led to reduced regulatory T cell (T-reg) numbers and impaired oral tolerance. We observed that ROR gamma t(+) innate lymphoid cells (ILCs) are the primary source of GM-CSF in the gut and that ILC-driven GM-CSF production was dependent on the ability of macrophages to sense microbial signals and produce interleukin-1 beta. Our findings reveal that commensal microbes promote a crosstalk between innate myeloid and lymphoid cells that leads to immune homeostasis in the intestine.
• 造血幹細胞移植後GVHDと消化管傷害

  早瀬英子, 橋本大吾, 豊嶋崇徳

  最新医学 69 (3) 503 - 507 2014/03 [Not refereed][Not invited]
  
• The miR-126-VEGFR2 axis controls the innate response to pathogen-associated nucleic acids

  Judith Agudo, Albert Ruzo, Navpreet Tung, Helene Salmon, Marylene Leboeuf, Daigo Hashimoto, Christian Becker, Lee-Ann Garrett-Sinha, Alessia Baccarini, Miriam Merad, Brian D. Brown

  NATURE IMMUNOLOGY 15 (1) 54 - 62 1529-2908 2014/01 [Refereed][Not invited]
   

  miR-126 is a microRNA expressed predominately by endothelial cells and controls angiogenesis. We found miR-126 was required for the innate response to pathogen-associated nucleic acids and that miR-126-deficient mice had greater susceptibility to infection with pseudotyped HIV. Profiling of miRNA indicated that miR-126 had high and specific expression by plasmacytoid dendritic cells (pDCs). Moreover, miR-126 controlled the survival and function of pDCs and regulated the expression of genes encoding molecules involved in the innate response, including Tlr7, Tlr9 and Nfkb1, as well as Kdr, which encodes the growth factor receptor VEGFR2. Deletion of Kdr in DCs resulted in reduced production of type I interferon, which supports the proposal of a role for VEGFR2 in miR-126 regulation of pDCs. Our studies identify the miR-126 VEGFR2 axis as an important regulator of the innate response that operates through multiscale control of pDCs.
• Expansion of donor-reactive host T cells in primary graft failure after allogeneic hematopoietic SCT following reduced-intensity conditioning

  M. Koyama, D. Hashimoto, K. Nagafuji, T. Eto, Y. Ohno, K. Aoyama, H. Iwasaki, T. Miyamoto, G. R. Hill, K. Akashi, T. Teshima

  BONE MARROW TRANSPLANTATION 49 (1) 110 - 115 0268-3369 2014/01 [Not refereed][Not invited]
   

  Graft rejection remains a major obstacle in allogeneic hematopoietic SCT following reduced-intensity conditioning (RIC-SCT), particularly after cord blood transplantation (CBT). In a murine MHC-mismatched model of RIC-SCT, primary graft rejection was associated with activation and expansion of donor-reactive host T cells in peripheral blood and BM early after SCT. Donor-derived dendritic cells are at least partly involved in host T-cell activation. We then evaluated if such an expansion of host T cells could be associated with graft rejection after RIC-CBT. Expansion of residual host lymphocytes was observed in 4/7 patients with graft rejection at 3 weeks after CBT, but in none of the 17 patients who achieved engraftment. These results suggest the crucial role of residual host T cells after RIC-SCT in graft rejection and expansion of host T cells could be a marker of graft rejection. Development of more efficient T cell-suppressive conditioning regimens may be necessary in the context of RIC-SCT.
• Reciprocal Expression of Enteric Antimicrobial Proteins in Intestinal Graft-Versus-Host Disease

  Yoshihiro Eriguchi, Hidetaka Uryu, Kiminori Nakamura, Sonoko Shimoji, Shuichiro Takashima, Hiromi Iwasaki, Toshihiro Miyamoto, Nobuyuki Shimono, Daigo Hashimoto, Koichi Akashi, Tokiyoshi Ayabe, Takanori Teshima

  BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION 19 (10) 1525 - 1529 1083-8791 2013/10 [Refereed][Not invited]
   

  We recently demonstrated that expression of alpha-defensins, the major antimicrobial peptides produced by Paneth cells, was severely suppressed in mice with graft-versus-host disease (GVHD). In this study, we found that antibacterial lectin, regenerating islet-derived III gamma (RegIII gamma) was upregulated in villous enterocytes, thus demonstrating the reciprocal control of enteric antimicrobial proteins in GVHD. Upregulation of RegIII gamma was mediated by a mechanism independent upon radiation-induced intestinal tract damage. MyD88-mediated signaling in intestinal epithelium was required for RegIII gamma upregulation in GVHD and antibiotic therapy downregulated RegIII gamma expression. These results suggest that MyD88-mediated sensing of the intestinal microbes disregulated in GVHD induces RegIII gamma upregulation in GVHD and argue a role for RegIII gamma in the pathogenesis of GVHD. (C) 2013 American Society for Blood and Marrow Transplantation.
• 血球トラフィッキングとGVHD

  橋本大吾, 豊嶋崇徳

  血液フロンティア 23 (10) 59 - 70 2013/10 [Not refereed][Not invited]
  
• CD169(+) macrophages provide a niche promoting erythropoiesis under homeostasis and stress

  Andrew Chow, Matthew Huggins, Jalal Ahmed, Daigo Hashimoto, Daniel Lucas, Yuya Kunisaki, Sandra Pinho, Marylene Leboeuf, Clara Noizat, Nico van Rooijen, Masato Tanaka, Zhizhuang Joe Zhao, Aviv Bergman, Miriam Merad, Paul S. Frenette

  NATURE MEDICINE 19 (4) 429 - + 1078-8956 2013/04 [Refereed][Not invited]
   

  A role for macrophages in erythropoiesis was suggested several decades ago when erythroblastic islands in the bone marrow, composed of a central macrophage surrounded by developing erythroblasts, were described. However, the in vivo role of macrophages in erythropoiesis under homeostatic conditions or in disease remains unclear. We found that specific depletion of CD169(+) macrophages markedly reduced the number of erythroblasts in the bone marrow but did not result in overt anemia under homeostatic conditions, probably because of concomitant alterations in red blood cell clearance. However, CD169(+) macrophage depletion significantly impaired erythropoietic recovery from hemolytic anemia, acute blood loss and myeloablation. Furthermore, macrophage depletion normalized the erythroid compartment in a JAK2(V617F)-driven mouse model of polycythemia vera, suggesting that erythropoiesis in polycythemia vera remains under the control of macrophages in the bone marrow and splenic microenvironments. These results indicate that CD169(+) macrophages promote late erythroid maturation and that modulation of the macrophage compartment may be a new strategy to treat erythropoietic disorders.
• Tissue-Resident Macrophages Self-Maintain Locally throughout Adult Life with Minimal Contribution from Circulating Monocytes

  Daigo Hashimoto, Andrew Chow, Clara Noizat, Pearline Teo, Mary Beth Beasley, Marylene Leboeuf, Christian D. Becker, Peter See, Jeremy Price, Daniel Lucas, Melanie Greter, Arthur Mortha, Scott W. Boyer, E. Camilla Forsberg, Masato Tanaka, Nico van Rooijen, Adolfo Garcia-Sastre, E. Richard Stanley, Florent Ginhoux, Paul S. Frenette, Miriam Merad

  IMMUNITY 38 (4) 792 - 804 1074-7613 2013/04 [Refereed][Not invited]
   

  Despite accumulating evidence suggesting local self-maintenance of tissue macrophages in the steady state, the dogma remains that tissue macrophages derive from monocytes. Using parabiosis and fate-mapping approaches, we confirmed that monocytes do not show significant contribution to tissue macrophages in the steady state. Similarly, we found that after depletion of lung macrophages, the majority of repopulation occurred by stochastic cellular proliferation in situ in a macrophage colony-stimulating factor (M-Csf)- and granulocyte macrophage (GM)-CSF-dependent manner but independently of interleukin-4. We also found that after bone marrow transplantation, host macrophages retained the capacity to expand when the development of donor macrophages was compromised. Expansion of host macrophages was functional and prevented the development of alveolar proteinosis in mice transplanted with GM-Csf-receptor-deficient progenitors. Collectively, these results indicate that tissue-resident macrophages and circulating monocytes should be classified as mononuclear phagocyte lineages that are independently maintained in the steady state.
• Cross-presenting CD103(+) dendritic cells are protected from influenza virus infection

  Julie Helft, Balaji Manicassamy, Pierre Guermonprez, Daigo Hashimoto, Aymeric Silvin, Judith Agudo, Brian D. Brown, Mirco Schmolke, Jennifer C. Miller, Marylene Leboeuf, Kenneth M. Murphy, Adolfo Garcia-Sastre, Miriam Merad

  JOURNAL OF CLINICAL INVESTIGATION 122 (11) 4037 - 4047 0021-9738 2012/11 [Refereed][Not invited]
   

  CD8(+) cytotoxic T cells are critical for viral clearance from the lungs upon influenza virus infection. The contribution of antigen cross-presentation by DCs to the induction of anti-viral cytotoxic T cells remains controversial. Here, we used a recombinant influenza virus expressing a nonstructural 1-GFP (NS1-GFP) reporter gene to visualize the route of antigen presentation by lung DCs upon viral infection in mice. We found that lung CD103(+) DCs were the only subset of cells that carried intact GFP protein to the draining LNs. Strikingly, lung migratory CD103(+) DCs were not productively infected by influenza virus and thus were able to induce virus-specific CD8(+) T cells through the cross-presentation of antigens from virally infected cells. We also observed that CD103(+) DC resistance to infection correlates with an increased anti-viral state in these cells that is dependent on the expression of type I IFN receptor. These results show that efficient cross-priming by migratory lung DCs is coupled to the acquisition of an anti-viral status, which is dependent on the type I IFN signaling pathway.
• Cross-presenting CD103(+) dendritic cells are protected from influenza virus infection

  Julie Helft, Balaji Manicassamy, Pierre Guermonprez, Daigo Hashimoto, Aymeric Silvin, Judith Agudo, Brian D. Brown, Mirco Schmolke, Jennifer C. Miller, Marylene Leboeuf, Kenneth M. Murphy, Adolfo Garcia-Sastre, Miriam Merad

  JOURNAL OF CLINICAL INVESTIGATION 122 (11) 4037 - 4047 0021-9738 2012/11 [Not refereed][Not invited]
   

  CD8(+) cytotoxic T cells are critical for viral clearance from the lungs upon influenza virus infection. The contribution of antigen cross-presentation by DCs to the induction of anti-viral cytotoxic T cells remains controversial. Here, we used a recombinant influenza virus expressing a nonstructural 1-GFP (NS1-GFP) reporter gene to visualize the route of antigen presentation by lung DCs upon viral infection in mice. We found that lung CD103(+) DCs were the only subset of cells that carried intact GFP protein to the draining LNs. Strikingly, lung migratory CD103(+) DCs were not productively infected by influenza virus and thus were able to induce virus-specific CD8(+) T cells through the cross-presentation of antigens from virally infected cells. We also observed that CD103(+) DC resistance to infection correlates with an increased anti-viral state in these cells that is dependent on the expression of type I IFN receptor. These results show that efficient cross-priming by migratory lung DCs is coupled to the acquisition of an anti-viral status, which is dependent on the type I IFN signaling pathway.
• Deciphering the transcriptional network of the dendritic cell lineage

  Jennifer C. Miller, Brian D. Brown, Tal Shay, Emmanuel L. Gautier, Vladimir Jojic, Ariella Cohain, Gaurav Pandey, Marylene Leboeuf, Kutlu G. Elpek, Julie Helft, Daigo Hashimoto, Andrew Chow, Jeremy Price, Melanie Greter, Milena Bogunovic, Angelique Bellemare-Pelletier, Paul S. Frenette, Gwendalyn J. Randolph, Shannon J. Turley, Miriam Merad

  NATURE IMMUNOLOGY 13 (9) 888 - 899 1529-2908 2012/09 [Refereed][Not invited]
   

  Although much progress has been made in the understanding of the ontogeny and function of dendritic cells (DCs), the transcriptional regulation of the lineage commitment and functional specialization of DCs in vivo remains poorly understood. We made a comprehensive comparative analysis of CD8(+), CD103(+), CD11b(+) and plasmacytoid DC subsets, as well as macrophage DC precursors and common DC precursors, across the entire immune system. Here we characterized candidate transcriptional activators involved in the commitment of myeloid progenitor cells to the DC lineage and predicted regulators of DC functional diversity in tissues. We identified a molecular signature that distinguished tissue DCs from macrophages. We also identified a transcriptional program expressed specifically during the steady-state migration of tissue DCs to the draining lymph nodes that may control tolerance to self tissue antigens.
• Adrenergic Nerves Govern Circadian Leukocyte Recruitment to Tissues

  Christoph Scheiermann, Yuya Kunisaki, Daniel Lucas, Andrew Chow, Jung-Eun Jang, Dachuan Zhang, Daigo Hashimoto, Miriam Merad, Paul S. Frenette

  IMMUNITY 37 (2) 290 - 301 1074-7613 2012/08 [Refereed][Not invited]
   

  The multistep sequence leading to leukocyte migration is thought to be locally regulated at the inflammatory site. Here, we show that broad systemic programs involving long-range signals from the sympathetic nervous system (SNS) delivered by adrenergic nerves regulate rhythmic recruitment of leukocytes in tissues. Constitutive leukocyte adhesion and migration in murine bone marrow (BM) and skeletal-muscle microvasculature fluctuated with circadian peak values at night. Migratory oscillations, altered by experimental jet lag, were implemented by perivascular SNS fibers acting on beta-adrenoreceptors expressed on nonhematopoietic cells and leading to tissue-specific, differential circadian oscillations in the expression of endothelial cell adhesion molecules and chemokines. We showed that these rhythms have physiological consequences through alteration of hematopoietic cell recruitment and overall survival in models of septic shock, sickle cell vaso-occlusion, and BM transplantation. These data provide unique insights in the leukocyte adhesion cascade and the potential for time-based therapeutics for transplantation and inflammatory diseases.
• Antigen-presenting cell-derived complement modulates graft-versus-host disease

  Wing-Hong Kwan, Daigo Hashimoto, Estela Paz-Artal, Katya Ostrow, Melanie Greter, Hugo Raedler, M. Edward Medof, Miriam Merad, Peter S. Heeger

  JOURNAL OF CLINICAL INVESTIGATION 122 (6) 2234 - 2238 0021-9738 2012/06 [Refereed][Not invited]
   

  Acute graft-versus-host disease (GvHD) is a serious complication of allogeneic hematopoietic cell transplantation (allo-HCT) that results from donor allogeneic T cell attack on host tissues. Based on previous work implicating immune cell-derived C3a and C5a as regulators of T cell immunity, we examined the effects of locally produced C3a and C5a on murine T cell-mediated GvHD. We found that total body irradiation, a conditioning regimen required to permit engraftment of allo-HCT, caused upregulation and activation of alternative pathway complement components by recipient APCs. Allo-HCT with decay accelerating factor-null (Daf1(-/-)) host BM and Daf1(-/-) donor lymphocytes led to exacerbated GvHD outcome and resulted in splenic and organ-infiltrating T cell expansion. T cells deficient in C3a receptor (C3aR) and/or C5a receptor (C5aR) responded weakly in allogeneic hosts and exhibited limited ability to induce GvHD. Using a clinically relevant treatment strategy, we showed that pharmacological C5aR blockade reduced GvHD morbidity. Our data mechanistically link APC-derived complement to T cell-mediated GvHD and support complement inhibition as a therapeutic strategy for GvHD in humans.
• GM-CSF Controls Nonlymphoid Tissue Dendritic Cell Homeostasis but Is Dispensable for the Differentiation of Inflammatory Dendritic Cells

  Melanie Greter, Julie Helft, Andrew Chow, Daigo Hashimoto, Arthur Mortha, Judith Agudo-Cantero, Milena Bogunovic, Emmanuel L. Gautier, Jennifer Miller, Marylene Leboeuf, Geming Lu, Costica Aloman, Brian D. Brown, Jeffrey W. Pollard, Huabao Xiong, Gwendalyn J. Randolph, Jerry E. Chipuk, Paul S. Frenette, Miriam Merad

  IMMUNITY 36 (6) 1031 - 1046 1074-7613 2012/06 [Refereed][Not invited]
   

  GM-CSF (Csf-2) is a critical cytokine for the in vitro generation of dendritic cells (DCs) and is thought to control the development of inflammatory DCs and resident CD103(+) DCs in some tissues. Here we showed that in contrast to the current understanding, Csf-2 receptor acts in the steady state to promote the survival and homeostasis of nonlymphoid tissue-resident CD103(+) and CD11b(+) DCs. Absence of Csf-2 receptor on lung DCs abrogated the induction of CD8(+) T cell immunity after immunization with particulate antigens. In contrast, Csf-2 receptor was dispensable for the differentiation and innate function of inflammatory DCs during acute injuries. Instead, inflammatory DCs required Csf-1 receptor for their development. Thus, Csf-2 is important in vaccine-induced CD8(+) T cell immunity through the regulation of nonlymphoid tissue DC homeostasis rather than control of inflammatory DCs in vivo.
• 同種抗原による移植片対白血病効果減弱のメカニズム

  朝倉 昇司, 橋本 大吾, 高嶋 秀一郎, 杉山 暖子, 前田 嘉信, 赤司 浩一, 谷本 光音, 豊嶋 崇徳

  岡山医学会雑誌 岡山医学会 124 (1) 5 - 8 0030-1558 2012/04
• R-Ras is required for murine dendritic cell maturation and CD4(+) T-cell priming

  Gobind Singh, Daigo Hashimoto, Xiaocai Yan, Julie Helft, Patricia J-Y Park, Ge Ma, Rui F. Qiao, Colin R. Kennedy, Shu-Hsia Chen, Miriam Merad, Andrew M. Chan

  BLOOD 119 (7) 1693 - 1701 0006-4971 2012/02 [Refereed][Not invited]
   

  R-Ras is a member of the RAS superfamily of small GTP-binding proteins. The physiologic function of R-Ras has not been fully elucidated. We found that R-Ras is expressed by lymphoid and nonlymphoid tissues and drastically upregulated when bone marrow progenitors are induced to differentiate into dendritic cells (DCs). To address the role of R-Ras in DC functions, we generated a R-Ras-deficient mouse strain. We found that tumors induced in Rras(-/-) mice formed with shorter latency and attained greater tumor volumes. This finding has prompted the investigation of a role for R-Ras in the immune system. Indeed, Rras(-/-) mice were impaired in their ability to prime allogeneic and antigen-specific T-cell responses. Rras(-/-) DCs expressed lower levels of surface MHC class II and CD86 in response to lipopolysaccharide compared with wild-type DCs. This was correlated with a reduced phosphorylation of p38 and Akt. Consistently, R-Ras-GTP level was increased within 10 minutes of lipopolysaccharide stimulation. Furthermore, Rras(-/-) DCs have attenuated capacity to spread on fibronectin and form stable immunologic synapses with T cells. Altogether, these findings provide the first demonstration of a role for R-Ras in cell-mediated immunity and further expand on the complexity of small G-protein signaling in DCs. (Blood.2012;119(7):1693-1701)
• Dendritic Cell and Macrophage Heterogeneity In Vivo

  Daigo Hashimoto, Jennifer Miller, Miriam Merad

  IMMUNITY 35 (3) 323 - 335 1074-7613 2011/09 [Refereed][Not invited]
   

  Macrophage and dendritic cell (DC) are hematopoietic cells found in all tissues in the steady state that share the ability to sample the environment but have distinct function in tissue immunity. Controversies remain on the best way to distinguish macrophages from DCs in vivo. In this Perspective, we discuss how recent discoveries in the origin of the DC and macrophage lineage help establish key functional differences between tissue DC and macrophage subsets. We also emphasize the need to further understand the functional heterogeneity of the tissue DC and macrophage lineages to better comprehend the complex role of these cells in tissue homeostasis and immunity.
• Pretransplant CSF-1 therapy expands recipient macrophages and ameliorates GVHD after allogeneic hematopoietic cell transplantation

  Daigo Hashimoto, Andrew Chow, Melanie Greter, Yvonne Saenger, Wing-Hong Kwan, Marylene Leboeuf, Florent Ginhoux, Jordi C. Ochando, Yuya Kunisaki, Nico van Rooijen, Chen Liu, Takanori Teshima, Peter S. Heeger, E. Richard Stanley, Paul S. Frenette, Miriam Merad

  JOURNAL OF EXPERIMENTAL MEDICINE 208 (5) 1069 - 1082 0022-1007 2011/05 [Refereed][Not invited]
   

  Acute graft-versus-host disease (GVHD) results from the attack of host tissues by donor allogeneic T cells and is the most serious limitation of allogeneic hematopoietic cell transplantation (allo-HCT). Host antigen-presenting cells are thought to control the priming of alloreactive T cells and the induction of acute GVHD after allo-HCT. However, whereas the role of host DC in GVHD has been established, the contribution of host macrophages to GVHD has not been clearly addressed. We show that, in contrast to DC, reducing of the host macrophage pool in recipient mice increased donor T cell expansion and aggravated GVHD mortality after allo-HCT. We also show that host macrophages that persist after allo-HCT engulf donor allogeneic T cells and inhibit their proliferation. Conversely, administration of the cytokine CSF-1 before transplant expanded the host macrophage pool, reduced donor T cell expansion, and improved GVHD morbidity and mortality after allo-HCT. This study establishes the unexpected key role of host macrophages in inhibiting GVHD and identifies CSF-1 as a potential prophylactic therapy to limit acute GVHD after allo-HCT in the clinic.
• Bone marrow CD169(+) macrophages promote the retention of hematopoietic stem and progenitor cells in the mesenchymal stem cell niche

  Andrew Chow, Daniel Lucas, Andres Hidalgo, Simon Mendez-Ferrer, Daigo Hashimoto, Christoph Scheiermann, Michela Battista, Marylene Leboeuf, Colette Prophete, Nico van Rooijen, Masato Tanaka, Miriam Merad, Paul S. Frenette

  JOURNAL OF EXPERIMENTAL MEDICINE 208 (2) 261 - 271 0022-1007 2011/02 [Refereed][Not invited]
   

  Hematopoietic stem cells (HSCs) reside in specialized bone marrow (BM) niches regulated by the sympathetic nervous system (SNS). Here, we have examined whether mononuclear phagocytes modulate the HSC niche. We defined three populations of BM mononuclear phagocytes that include Gr-1(hi) monocytes (MOs), Gr-1(lo) MOs, and macrophages (M Phi) based on differential expression of Gr-1, CD115, F4/80, and CD169. Using MO and M Phi conditional depletion models, we found that reductions in BM mononuclear phagocytes led to reduced BM CXCL12 levels, the selective down-regulation of HSC retention genes in Nestin(+) niche cells, and egress of HSCs/progenitors to the bloodstream. Furthermore, specific depletion of CD169(+) M Phi, which spares BM MOs, was sufficient to induce HSC/progenitor egress. M Phi depletion also enhanced mobilization induced by a CXCR4 antagonist or granulocyte colony-stimulating factor. These results highlight two antagonistic, tightly balanced pathways that regulate maintenance of HSCs/progenitors in the niche during homeostasis, in which M Phi cross talk with the Nestin(+) niche cell promotes retention, and in contrast, SNS signals enhance egress. Thus, strategies that target BM M Phi hold the potential to augment stem cell yields in patients that mobilize HSCs/progenitors poorly.
• Harnessing dendritic cells to improve allogeneic hematopoietic cell transplantation outcome

  Daigo Hashimoto, Miriam Merad

  SEMINARS IN IMMUNOLOGY 23 (1) 50 - 57 1044-5323 2011/02 [Refereed][Not invited]
   

  In clinical practice, hematopoietic cell transplantation (HCT) is now recognized as a powerful means of delivering effective cellular immunotherapy for malignant and non-malignant diseases. In patients with severe hematological malignancies, the success of allogeneic HCT is largely based on immunologic graft-versus-tumor (GVT) effects mediated by allogeneic T lymphocytes present in the graft. Unfortunately, this beneficial effect is counterbalanced by the occurrence of graft versus host reactions directed against normal host tissues resulting in graft versus host disease (GVHD), a potentially life-threatening complication that limits the success of allogeneic HCT. Therefore, while preserving beneficial GVT effects, a major objective in allogeneic HCT is the prevention of GVHD. Studies in the last decade revealed the central role of dendritic cells and macrophages in modulating graft versus host immune reactions after allogeneic HCT. In this review, we summarize recent progress and potential new therapeutic avenues using dendritic cell-based strategies to improve allogeneic HCT outcome. (C) 2011 Elsevier Ltd. All rights reserved.
• Bone marrow CD169(+) macrophages promote the retention of hematopoietic stem and progenitor cells in the mesenchymal stem cell niche

  Andrew Chow, Daniel Lucas, Andres Hidalgo, Simon Mendez-Ferrer, Daigo Hashimoto, Christoph Scheiermann, Michela Battista, Marylene Leboeuf, Colette Prophete, Nico van Rooijen, Masato Tanaka, Miriam Merad, Paul S. Frenette

  JOURNAL OF EXPERIMENTAL MEDICINE 208 (2) 261 - 271 0022-1007 2011/02 [Not refereed][Not invited]
   

  Hematopoietic stem cells (HSCs) reside in specialized bone marrow (BM) niches regulated by the sympathetic nervous system (SNS). Here, we have examined whether mononuclear phagocytes modulate the HSC niche. We defined three populations of BM mononuclear phagocytes that include Gr-1(hi) monocytes (MOs), Gr-1(lo) MOs, and macrophages (M Phi) based on differential expression of Gr-1, CD115, F4/80, and CD169. Using MO and M Phi conditional depletion models, we found that reductions in BM mononuclear phagocytes led to reduced BM CXCL12 levels, the selective down-regulation of HSC retention genes in Nestin(+) niche cells, and egress of HSCs/progenitors to the bloodstream. Furthermore, specific depletion of CD169(+) M Phi, which spares BM MOs, was sufficient to induce HSC/progenitor egress. M Phi depletion also enhanced mobilization induced by a CXCR4 antagonist or granulocyte colony-stimulating factor. These results highlight two antagonistic, tightly balanced pathways that regulate maintenance of HSCs/progenitors in the niche during homeostasis, in which M Phi cross talk with the Nestin(+) niche cell promotes retention, and in contrast, SNS signals enhance egress. Thus, strategies that target BM M Phi hold the potential to augment stem cell yields in patients that mobilize HSCs/progenitors poorly.
• Alloantigen expression on non-hematopoietic cells reduces graft-versus-leukemia effects in mice

  Shoji Asakura, Daigo Hashimoto, Shuichiro Takashima, Haruko Sugiyama, Yoshinobu Maeda, Koichi Akashi, Mitsune Tanimoto, Takanori Teshima

  JOURNAL OF CLINICAL INVESTIGATION 120 (7) 2370 - 2378 0021-9738 2010/07 [Refereed][Not invited]
   

  Allogeneic hematopoietic stem cell transplantation (HSCT) is used effectively to treat a number of hematological malignancies. Its beneficial effects rely on donor-derived T cell-targeted leukemic cells, the so-called graft-versus-leukemia (GVL) effect. Induction of GVL is usually associated with concomitant development of graft-versus-host disease (GVHD), a major complication of allogeneic HSCT. The T cells that mediate GVL and GVHD are activated by alloantigen presented on host antigen-presenting cells of hematopoietic origin, and it is not well understood how alloantigen expression on non-hematopoietic cells affects GVL activity. Here we show, in mouse models of MHC-matched, minor histocompatibility antigen-mismatched bone marrow transplantation, that alloantigen expression on host epithelium drives donor T cells into apoptosis and dysfunction during GVHD, resulting in a loss of GVL activity. During GVHD, programmed death-1 (PD-1) and PD ligand-1 (PD-L1), molecules implicated in inducing T cell exhaustion, were upregulated on activated T cells and the target tissue, respectively, suggesting that the T cell defects driven by host epithelial alloantigen expression might be mediated by the PD-1/PD-L1 pathway. Consistent with this, blockade of PD-1/PD-L1 interactions partially restored T cell effector functions and improved GVL. These results elucidate a previously unrecognized significance of alloantigen expression on non-hematopoietic cells in GVL and suggest that separation of GVL from GVHD for more effective HSCT may be possible in human patients.
• Monocytic suppressive cells mediate cardiovascular transplantation tolerance in mice

  Mercedes Rodriguez Garcia, Levi Ledgerwood, Yu Yang, Jiangnan Xu, Girdhari Lal, Bryna Burrell, Ge Ma, Daigo Hashimoto, Yansui Li, Peter Boros, Marcos Grisotto, Nico van Rooijen, Rafael Matesanz, Frank Tacke, Florent Ginhoux, Yaozhong Ding, Shu-Hsia Chen, Gwendalyn Randolph, Miriam Merad, Jonathan S. Bromberg, Jordi C. Ochando

  JOURNAL OF CLINICAL INVESTIGATION 120 (7) 2486 - 2496 0021-9738 2010/07 [Refereed][Not invited]
   

  One of the main unresolved questions in solid organ transplantation is how to establish indefinite graft survival that is free from long-term treatment with immunosuppressive drugs and chronic rejection (i.e., the establishment of tolerance). The failure to achieve this goal may be related to the difficulty in identifying the phenotype and function of the cell subsets that participate in the induction of tolerance. To address this issue, we investigated the suppressive roles of recipient myeloid cells that may be manipulated to induce tolerance to transplanted hearts in mice. Using depleting mAbs, clodronate-loaded liposomes, and transgenic mice specific for depletion of CD11c(+), CD11b(+), or CD115(+) cells, we identified a tolerogenic role for CD11b(+)CD115(+)Gr1(+) monocytes during the induction of tolerance by costimulatory blockade with CD40L-specific mAb. Early after transplantation, Gr1(+) monocytes migrated from the bone marrow into the transplanted organ, where they prevented the initiation of adaptive immune responses that lead to allograft rejection and participated in the development of Tregs. Our results suggest that mobilization of bone marrow CD11b(+)CD115(+)Gr1(+) monocytes under sterile inflammatory conditions mediates the induction of indefinite allograft survival. We propose that manipulating the common bone marrow monocyte progenitor could be a useful clinical therapeutic approach for inducing transplantation tolerance.
• The origin and development of nonlymphoid tissue CD103(+) DCs

  Florent Ginhoux, Kang Liu, Julie Helft, Milena Bogunovic, Melanie Greter, Daigo Hashimoto, Jeremy Price, Na Yin, Jonathan Bromberg, Sergio A. Lira, E. Richard Stanley, Michel Nussenzweig, Miriam Merad

  JOURNAL OF EXPERIMENTAL MEDICINE 206 (13) 3115 - 3130 0022-1007 2009/12 [Refereed][Not invited]
   

  CD103(+) dendritic cells (DCs) in nonlymphoid tissues are specialized in the cross-presentation of cell-associated antigens. However, little is known about the mechanisms that regulate the development of these cells. We show that two populations of CD11c(+)MHCII(+) cells separated on the basis of CD103 and CD11b expression coexist in most nonlymphoid tissues with the exception of the lamina propria. CD103(+) DCs are related to lymphoid organ CD8(+) DCs in that they are derived exclusively from pre-DCs under the control of fms-like tyrosine kinase 3 (Flt3) ligand, inhibitor of DNA protein 2 (Id2), and IFN regulatory protein 8 (IRF8). In contrast, lamina propria CD103(+) DCs express CD11b and develop independently of Id2 and IRF8. The other population of CD11c(+)MHCII(+) cells in tissues, which is CD103(-)CD11b(+), is heterogenous and depends on both Flt3 and MCSF-R. Our results reveal that nonlymphoid tissue CD103(+) DCs and lymphoid organ CD8(+) DCs derive from the same precursor and follow a related differentiation program.
• Origin of the Lamina Propria Dendritic Cell Network

  Milena Bogunovic, Florent Ginhoux, Julie Helft, Limin Shang, Daigo Hashimoto, Melanie Greter, Kang Liu, Claudia Jakubzick, Molly A. Ingersoll, Marylene Leboeuf, E. Richard Stanley, Michel Nussenzweig, Sergio A. Lira, Gwendalyn J. Randolph, Miriam Merad

  IMMUNITY 31 (3) 513 - 525 1074-7613 2009/09 [Refereed][Not invited]
   

  CX(3)CR1(+) and CD103(+) dendritic cells (DCs) in intestinal lamina propria play a key role in mucosal immunity. However, the origin and the developmental pathways that regulate their differentiation in the lamina propria remain unclear. We showed that monocytes gave rise exclusively to CD103(-)CX(3)CR1(+) lamina propria DCs under the control of macrophage-colony-stimulating factor receptor (M-CSFR) and Fms-like thyrosine kinase 3 (FIt3) ligands. In contrast, common DC progenitors (CDP) and pre-DCs, which give rise to lymphoid organ DCs but not to monocytes, differentiated exclusively into CD103(+)CX(3)CR1(-) lamina propria DCs under the control of FIt3 and granulocyte-macrophage-colony-stimulating factor receptor (GM-CSFR) ligands. CD103(+)CX(3)CR1(-) DCs but not CD103(-)CX(3)CR1(+) DCs in the lamina propria constitutively expressed CCR7 and were the first DCs to transport pathogenic Salmonella from the intestinal tract to the mesenteric lymph nodes. Altogether, these results underline the diverse origin of the lamina propria DC network and identify mucosal DCs that arise from pre-DCs as key sentinels of the gut immune system.
• Improved outcome of allogeneic bone marrow transplantation due to breastfeeding-induced tolerance to maternal antigens

  Kazutoshi Aoyama, Motoko Koyama, Ken-ichi Matsuoka, Daigo Hashimoto, Tatsuo Ichinohe, Mine Harada, Koichi Akashi, Mitsune Tanimoto, Takanori Teshima

  BLOOD 113 (8) 1829 - 1833 0006-4971 2009/02 [Refereed][Not invited]
   

  Exposure of offspring to noninherited maternal antigens (NIMAs) during pregnancy may have an impact on transplantations performed later in life. Using a mouse model, we recently showed that bone marrow transplantation (BMT) from NIMA-exposed offspring to the mother led to a reduction of graft-versus-host disease (GVHD). Since offspring can also be exposed to NIMAs by breastfeeding after birth, we tested whether breast milk could mediate the tolerogenic NIMA effect. We found that oral exposure to NIMAs by breastfeeding alone was sufficient to reduce GVHD, and that in utero exposure to NIMAs is required for maximum reduction of GVHD. The tolerogenic milk effects disappeared when donor mice were injected with CD25 monoclonal antibodies during the lactation period, suggesting a CD4(+)CD25(+) regulatory T cell dependent mechanism. Our results suggest a previously unknown impact of breastfeeding on the outcome of transplantation. (Blood. 2009;113:1829-1833)
• Plasmacytoid dendritic cells prime alloreactive T cells to mediate graft-versus-host disease as antigen-presenting cells

  Motoko Koyama, Daigo Hashimoto, Kazutoshi Aoyama, Ken-ichi Matsuoka, Kennosuke Karube, Hiroaki Niiro, Mine Harada, Mitsune Tanimoto, Koichi Akashi, Takanori Teshima

  BLOOD 113 (9) 2088 - 2095 0006-4971 2009/02 [Refereed][Not invited]
   

  Dendritic cells (DCs) can be classified into 2 distinct subsets: conventional DCs (cDCs) and plasmacytoid DCs (pDCs). cDCs can prime antigen-specific T-cell immunity, whereas in vivo function of pDCs as antigen-presenting cells remains controversial. We evaluated the contribution of pDCs to allogeneic T-cell responses in vivo in mouse models of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation by an add-back study of MHC-expressing pDCs into major histocompatibility complex-deficient mice that were resistant to GVHD. Alloantigen expression on pDCs alone was sufficient to prime alloreactive T cells and cause GVHD. An inflammatory environment created by host irradiation has the decisive role in maturing pDCs for T-cell priming but this process does not require Toll-like receptor signaling. Thus, functional outcomes of pDC-T-cell interactions depend on the immunologic context of encounter. To our knowledge, these results are the first to directly demonstrate an in vivo pathogenic role of pDCs as antigen-presenting cells in an antigen-specific T cell-mediated disease in the absence of other DC subsets and to provide important insight into developing strategies for tolerance induction in transplantation. (Blood. 2009; 113: 2088-2095)
• Sentiment sentence extraction using a hierarchical directed acyclic graph structure and a bootstrap approach

  Kazutaka Shimada, Daigo Hashimoto, Tsutomu Endo

  Proceedings of the 22nd Pacific Asia Conference on Language, Information and Computation, PACLIC 22 341 - 349 2008/12/01 [Not refereed][Not invited]
   

  As the World Wide Web rapidly grows, a huge number of online documents are easily accessible on the Web. We obtain a huge number of review documents that include user's opinions for products. To classify the opinions is one of the hottest topics in natural language processing. In general, we need a large amount of training data for the classification process. However, construction of training data by hand is costly. The goal of our study is to construct a sentiment tagging tool for particular domains. In this paper, we propose a method of sentiment sentence extraction for the 1st step of the system. For the task, we use a Hierarchical Directed Acyclic Graph (HDAG) structure. We obtained high accuracy with the graph based approach. Furthermore, we apply a bootstrap approach to the sentiment sentence extraction process. The experimental result shows the effectiveness of the method. © 2008 by Kazutaka Shimada, Daigo Hashimoto, and Tsutomu Endo.
• ドナーT細胞のToll-like Receptor(TLR)シグナルはGVHDの重症化に関与する

  青山 一利, 小山 幹子, 橋本 大吾, 佐古田 幸美, 竹田 潔, 赤司 浩一, 原田 実根, 谷本 光音, 豊嶋 崇徳

  臨床血液 (一社)日本血液学会-東京事務局 49 (9) 891 - 891 0485-1439 2008/09
• Allogeneic hematopoietic stem cell transplantation from an HLA-haploidentical related donor based on feto-maternal tolerance

  MATSUOKA Ken-ichi, AOYAMA Kazutoshi, KOYAMA Motoko, HASHIMOTO Daigo, ASAKURA Shoji, ICHINOHE Tatsuo, TANIMOTO Mitsune, TESHIMA Takanori

  Journal of Okayama Medical Association 岡山医学会 120 (1) 23 - 28 0030-1558 2008/05/01 [Not refereed][Not invited]
  
• Donor-derived thymic-dependent T cells cause chronic graft-versus-host disease

  Yukimi Sakoda, Daigo Hashimoto, Shoji Asakura, Kengo Takeuchi, Mine Harada, Mitsune Tanimoto, Takanori Teshima

  BLOOD 109 (4) 1756 - 1764 0006-4971 2007/02 [Refereed][Not invited]
   

  Chronic graft-versus-host disease (GVHD) is the most common cause of poor long-term outcomes after allogeneic bone marrow transplantation (BMT), but the pathophysiology of chronic GVHD still remains poorly understood. We tested the hypothesis that the impaired thymic negative selection of the recipients will permit the emergence of pathogenic T cells that cause chronic GVHD. Lethally irradiated C3H/HeN (H-2(k)) recipients were reconstituted with T-cell-depleted bone marrow cells from major histocompatibility complex [MHC] class II-deficient (H2-Ab1(-/-)) B6 (H-2(b)) mice. These mice developed diseases that showed all of the clinical and histopathological features of human chronic GVHD. Thymectomy prevented chronic GVHD, thus confirming the causal association of the thymus. CD4(+) T cells isolated from chronic GVHD mice were primarily donor reactive, and adoptive transfer of CD4(+) T cells generated in these mice caused chronic GVHD in C3H/HeN mice in the presence of B6-derived antigen-presenting cells. Our results demonstrate for the first time that T cells that escape from negative thymic selection could cause chronic GVHD after allogeneic BMT. These results also suggest that self-reactivity of donor T cells plays a role in this chronic GVHD, and improvement in the thymic function may have a potential to decrease chronic GVHD. (Blood. 2007;109:1756-1764) (c) 2007 by The American Society of Hematology.
• Lymphopenia-induced proliferation of donor T cells reduces their capacity for causing acute graft-versus-host disease

  Yoshinobu Maeda, Isao Tawara, Takanori Teshima, Chen Liu, Daigo Hashimoto, Ken-ichi Matsuoka, Mitsune Tanimoto, Pavan Reddy

  EXPERIMENTAL HEMATOLOGY 35 (2) 274 - 286 0301-472X 2007/02 [Refereed][Not invited]
   

  Objective. T cells that undergo lymphopenia-induced proliferation (LIP) are characterized by greater effector and anti-tumor function than naive T cells. But the ability of these T cells in causing graft-versus-host disease (GVHD) is not known. Methods. We tested the hypothesis that donor T cells that had undergone LIP would cause more severe GVHD than naive T cells by utilizing well-characterized murine experimental models of allogeneic bone marrow transplantation (BMT). Results. Contrary to our hypothesis, LIP of donor T cells under either noninflammatory or irradiated conditions caused significantly reduced GVHD as determined by survival, clinical, pathologic, and biochemical parameters than naive T cells. Compared to naive donor T cells, LIP T cells demonstrated reduced expansion in vivo and in vitro after allogeneic BMT. The reduction in GVHD mortality and severity was observed across multiple strains after allogeneic BMT. In vivo mechanistic studies by cell depletion demonstrated an increase in the CD44(hi) "memory" phenotype T cells and not the CD4(+)CD25(+) T cell subset to be critical for the reduction in GVHD. Conclusions. These data demonstrate that LIP of T cells regulates acute GVHD severity in contrast to their ability to cause increased allograft rejection, autoimmunity, or anti-tumor immunity. (c) 2007 International Society for Experimental Hematology. Published by Elsevier Inc.
• ドナー造血幹細胞由来細胞が慢性graft-versus-host disease(GVHD)を起こす

  佐古田 幸美, 橋本 大吾, 朝倉 昇司, 竹内 賢吾, 原田 実根, 谷本 光音, 豊嶋 崇徳

  日本内科学会雑誌 (一社)日本内科学会 96 (Suppl.) 156 - 156 0021-5384 2007/02
• FTY720 enhances the activation-induced apoptosis of donor T cells and modulates graft-versus-host disease

  Daigo Hashimoto, Shoji Asakura, Ken-ichi Matsuoka, Yukimi Sakoda, Motoko Koyama, Kazutoshi Aoyama, Mitsune Tanimoto, Takanori Teshima

  EUROPEAN JOURNAL OF IMMUNOLOGY 37 (1) 271 - 281 0014-2980 2007/01 [Refereed][Not invited]
   

  FTY720 is a novel immunosuppressant that improves the outcomes after solid organ and bone marrow transplantation (BMT) due to the sequestration of T cells into LN. We tested the hypothesis that the sequestration of donor T cells in LN by FTY720 would enhance their interaction with host APC, thus causing a greater degree of activation-induced apoptosis of alloreactive T cells, and thereby resulting in a reduction of graft-vs.-host disease (GVHD). The short-term administration of FTY720 improved the recipient survival after allogeneic BMT. FTY720 treatment facilitated a rapid contraction of the donor T cell pool in association with an increased degree of apoptosis of donor T cells. The donor T cell reactivity to host alloantigens was diminished in host's LN and adoptive transfer of donor T cells isolated from LN of FTY720-treated recipients of allogeneic BMT induced less severe GVHD in secondary recipients than the transfer from controls. Caspase-dependent apoptosis was involved in this mechanism because FTY720-induced protection was abrogated when a pan-caspase inhibitor was administered. These findings thus demonstrate the presence of a novel mechanism by which FTY720 modulates the allogeneic T cell responses: namely, by the induction of activation-induced apoptosis of alloreactive T cells in LN.
• Breast-feeding mediates feto-maternal tolerance and improves outcome of allogeneic bone marrow transplantation

  Aoyama, Kazutoshi, Matsuoka, Ken-ichi, Hashimoto, Daigo, Ichinohe, Tatsuo, Harada, Mine, Tanimoto, Mitsune, Teshima, Takanori

  BLOOD 110 (11) 644A - 644A 0006-4971 2007 [Not refereed][Not invited]
  
• BONE MARROW PROCESSING IN ABO-INCOMPATIBLE BONE MARROW TRANSPLANTATION USING COBE SPECTRA CELL SEPARATOR

  HENZAN Tomoko, MIYAMOTO Toshihiro, IZUMI Ken-ichi, NUMATA Akihiko, KAMEZAKI Kenjiro, YAMASAKI Satoshi, KIYOSHIMA Kumi, MIYAMOTO Kyoko, HASHIMOTO Daigo, IWASAKI Junko, IWASAKI Hiromi, NAGAFUJI Koji, HARADA Mine, INABA Shoichi, TESHIMA Takanori, AKASHI Koichi

  Japanese Journal of Transfusion and Cell Therapy The Japan Society of Transfusion Medicine and Cell Therapy 52 (6) 693 - 697 1881-3011 2006/12/20 [Not refereed][Not invited]
   

  In ABO major incompatibility between a donor and a recipient on bone marrow transplantation (BMT), red blood cells (RBC) and/or plasma containing anti-A and anti-B antibodies should be removed from collected marrow aspirates to prevent hemolytic reactions. We processed 20 marrow aspirates to concentrate mononuclear cells using a COBE Spectra cell separator. BM processing resulted in a mean recovery of 34.0±8.38% of mononuclear cells and 112.3±36.3% of CD34+ cells in the final product. A mean of 98.4% of RBC was removed, with a mean of 4.2±2.4ml of RBC in the final product. Twenty patients receiving allogenic BMT showed no sign of hemolysis and a rapid hematopoietic recovery after BMT. BM processing using the COBE spectra cell separator proved to be a fast, safe, and effective procedure to remove RBC and plasma from the marrow harvest in ABO-incompatible BMT.
• FTY720によるマウス同種骨髄移植後のドナーリンパ球のアポトーシス誘導とGVHD予防

  橋本 大吾, 朝倉 昇司, 松岡 賢市, 佐古田 幸美, 小山 幹子, 青山 一利, 谷本 光音, 赤司 浩一, 豊嶋 崇徳

  臨床血液 (一社)日本血液学会-東京事務局 47 (9) 1017 - 1017 0485-1439 2006/09
• Transient respiratory disturbance by granulocyte-colony-stimulating factor administration in healthy donors of allogeneic peripheral blood progenitor cell transplantation

  Yoshida, I, K Matsuo, T Teshima, D Hashimoto, Y Tanimoto, M Harada, M Tanimoto

  TRANSFUSION 46 (2) 186 - 192 0041-1132 2006/02 [Refereed][Not invited]
   

  BACKGROUND: Allogeneic peripheral blood progenitor cell (PBPC) transplantation requires granulocyte-colony-stimulating factor (G-CSF) administration to mobilize PBPCs in healthy donors. The effects of G-CSF on pulmonary functions, however, have not been clearly elucidated in PBPC donors. STUDY DESIGN AND METHODS: Respiratory status by measurements of arterial blood gas was prospectively evaluated serially in 25 healthy donors (9 men, 16 women; age, 18-61 years) administered a dose of 10 mu g per kg for 5 days. RESULTS: White blood cell (WBC) counts increased in all the subjects after G-CSF administration; means on Days 0, 3, and 5 were 6 x 10(9), 33.4 x 10(9), and 33.6 x 10(9) per L, respectively. The mean PaO2 values on the respective days were 93.1, 85.8, and 81.8 mmHg, and these changes were significant (p < 0.0001), remaining significant after adjustment for the WBC count. Levels of both PaCO2 and AaDO(2) were significantly higher after G-CSF administration than those before G-CSF administration (p < 0.0001 and p = 0.0004, respectively). SaO(2) was significantly decreased after G-CSF administration (p = 0.0002). Age was identified as a significant predictive factor for the increase of AaDO(2) and PaO2 decline. These observations clearly indicate that the gas exchange was significantly affected during G-CSF administration in healthy PBPC donors. CONCLUSION: Considering an increasing use of PBPC mobilization by G-CSF, careful monitoring of the respiratory status is important to ensure safety of PBPC donors, especially elderly donors.
• Fetal tolerance to maternal antigens improves the outcome of allogeneic bone marrow transplantation by a CD4(+)CD25(+) T-cell-dependent mechanism

  K Matsuoka, T Ichinohe, D Hashimoto, S Asakura, M Tanimoto, T Teshima

  BLOOD 107 (1) 404 - 409 0006-4971 2006/01 [Refereed][Not invited]
   

  The lack of donor availability is a major limitation to the widespread use of allogeneic hematopoietic stem cell transplantation, and therefore it would be beneficial to identify less immunogenic HLA mismatches. The maternal and fetal antigens that are transmitted through the bidirectional transplacental passage during pregnancy may induce tolerance to noninherited maternal antigens (NIMAs) in offspring and to inherited paternal antigens (IPAs) in the mother. Using mouse models of bone marrow transplantation (BMT), we found that a "child-to-mother" BMT from a NIMA-exposed donor reduced the morbidity and mortality of graft-versus-host disease in an antigen-specific manner; however, a "mother-to-child" BMT from an IPA-exposed donor did not. The NIMA-complementary BMT preserved the graft-versus-leukemia effects and favored the immune reconstitution, thus resulting in a marked improvement of the outcome after BMT. These tolerogenic NIMA effects were completely abolished by the depletion of CD4(+)CD25(+) cells from the donor inocula, thus suggesting the involvement of CD4(+)CD25(+) regulatory T cells in the tolerogenic NIMA effects. Our findings may therefore have profound implications on the performance of clinical BMT while also potentially helping to develop new strategies for using a NIMA-mismatched donor in the absence of an HLA-identical donor.
• Stimulation of host NKT cells by synthetic glycolipid regulates acute graft-versus-host disease by inducing Th2 polarization of donor T cells

  D Hashimoto, S Asakura, S Miyake, T Yamamura, L Van Kaer, C Liu, M Tanimoto, T Teshima

  JOURNAL OF IMMUNOLOGY 174 (1) 551 - 556 0022-1767 2005/01 [Refereed][Not invited]
   

  NKT cells are a unique immunoregulatory T cell population that produces large amounts of cytokines. We have investigated whether stimulation of host NKT cells could modulate acute graft-vs-host disease (GVHD) in mice. Injection of the synthetic NKT cell ligand alpha-galactosylceramide (alpha-GalCer) to recipient mice on day 0 following allogeneic bone marrow transplantation promoted Th2 polarization of donor T cells and a dramatic reduction of serum TNF-alpha, a critical mediator of GVHD. A single injection of alpha-GalCer to recipient mice significantly reduced morbidity and mortality of GVHD. However, the same treatment was unable to confer protection against GVHD in NKT cell-deficient CD1d knockout (CDld(-/-)) or IL-4(-/-) recipient mice or when STAT6(-/-)mice were used as donors, indicating the critical role of host NKT cells, host production of IL-4, and Th2 cytokine responses mediated by donor T cells on the protective effects of alpha-GalCer against GVHD. Thus, stimulation of host NKT cells through administration of NKT ligand can regulate acute GVHD by inducing Th2 polarization of donor T cells via STAT6-dependent mechanisms and might represent a novel strategy for prevention of acute GVHD.
• Paclitaxel administered weekly in patients with docetaxel-resistant metastatic breast cancer: A single-center study

  M Sawaki, Y Ito, D Hashimoto, N Mizunuma, S Takahashi, N Horikoshi, K Tada, F Kasumi, F Akiyama, G Sakamoto, T Imai, A Nakao, K Hatake

  TUMORI 90 (1) 36 - 39 0300-8916 2004/01 [Refereed][Not invited]
   

  Aims and background: We evaluated retrospectively the efficacy and toxicity of paclitaxel in patients with docetaxel-resistant metastatic breast cancer. Study design: Paclitaxel (80 mg/m(2)) was administered weekly to 44 patients who had previously received chemotherapy regimens for metastatic breast cancer. All patients had progressive disease in spite of having received docetaxel therapy. Results: Treatment was repeated until there was evidence of disease progression. Objective responses were obtained in 14 of 44 assessable patients (31.8%; 95% confidence interval, 17.5-46.1). Fourteen patients had partial responses; none responded completely. Seven of 14 responders had primary resistance to docetaxel therapy. The median duration of response was 6.1 months (range, 2.1-12.7). The median time to progression was 5.0 months. Clinically severe adverse events (grade 3 or 4) included neutropenia (27.2%), leukopenia (25.0%), neuropathy-sensory (13.6%), febrile neutropenia (6.8%), anemia (2.2%), constipation (2.2%), and edema (2.2%). Treatment was generally well tolerated and could be continued on an out-patient basis. Conclusions: Weekly paclitaxel is effective in patients with docetaxel-resistant metastatic breast cancer. This observation suggests partial cross-resistance between paclitaxel and docetaxel. There was no evidence for additive cumulative toxic effects of the two taxanes.
• Successful treatment with cyclosporin A of myelodysplastic syndrome with erythroid hypoplasia associated with t(6;8)(q15;q22)

  S Takata, K Kojima, N Fujii, K Kaneda, C Yoshida, D Hashimoto, S Asakura, K Shinagawa, M Tanimoto

  CANCER GENETICS AND CYTOGENETICS 140 (2) 167 - 169 0165-4608 2003/01 [Refereed][Not invited]
   

  We report a t(6;8)(q15;q22) in a patient with myelodysplastic syndrome (MDS) with erythroid hypoplasia. The patient was successfully treated with an immunosuppressive treatment with cyclosporin A, while the translocation was repeatedly detected as the sole anomaly with the percentages of positive cells ranging from 5% to 70%. To our knowledge, the t(6;8) has never been described in MDS. (C) 2003 Elsevier Science Inc. All rights reserved.

MISC

• A case of CBT for HSTCL who had been treated with infliximab for Crohn’s disease

  鈴木陶磨, 大東寛幸, 宮下直樹, 須藤啓斗, 日高大輔, 小笠原励起, 杉田純一, 小野澤真弘, 橋本大吾, 豊嶋崇徳  日本造血・免疫細胞療法学会総会プログラム・抄録集  44th-  2022
• Outcome of allogeneic hematopoietic stem cell transplantation for follicular lymphoma relapsing after autologous transplantation: analysis of the Japan Society for Hematopoietic Cell Transplantation

  Masatoshi Sakurai, Takehiko Mori, Koji Kato, Minoru Kanaya, Shohei Mizuno, Souichi Shiratori, Toshio Wakayama, Naoyuki Uchida, Hikaru Kobayashi, Kohmei Kubo, Itsuto Amano, Takanori Ohta, Yasuhiko Miyazaki, Junya Kanda, Takahiro Fukuda, Yoshiko Atsuta, Eisei Kondo, Yoshiaki Usui, Harumi Kato, Hirofumi Taji, Shohei Mizuno, Kiyohito Hayashi, Yuichiro Nawa, Risa Hashida, Daigo Hashimoto, Hideki Goto, Takahito Kawata, Minoru Kanaya, Kazutaka Ozeki, Kodai Kuriyama, Marie Ohbiki, Kazunori Imada, Shinichi Kako, Kana Sakamoto, Kazuaki Kameda, Kazuki Yoshimura, Hideaki Nitta, Yasunobu Sekiguchi, Hiroyuki Takahashi, Rika Sakai, Shuichi Mizuta, Hiroyuki Takamatsu, Risa Shimizu-Koresawa, Keisuke Kataoka, Nobuhiro Hiramoto, Kimimori Kamijo, Masashi Nishikubo, Fumiya Wada, Junji Suzumiya, Kazunari Aoki, Mizuki Watanabe, Tomoyasu Jo, Yusuke Toda, Yutaka Shimazu, Hiroatsu Ago, Kana Miyazaki, Tomohiko Aoki, Shunsuke Kunou, Koji Izutsu, Tatsuya Suzuki, Sung Won Kim, Satoshi Yamasaki, Hiroatsu Iida, Isao Yoshida, Akihiro Yokoyama, Yoshitaka Asakura, Kazuki Sakatoku, Hiroyasu Ogawa, Kenjiro Mitsuhashi, Takahiro Okada, Tsutomu Takahashi, Ritsuro Suzuki, Ayumi Fujimoto, Fumihiro Ishida, Takashi Ikeda, Kanako Yoshitsugu, Ikue Shiki, Shingo Yano, Yutaro Kamiyama, Dai Chihara, Akihito Nagata, Michiho Ebihara, Shinohara Akihito, Daisuke Kaji, Go Yamamoto, Satoko Morishima, Shinobu Tamura  Bone Marrow Transplantation  56-  (6)  1462  -1466  2021/06
• Progressive multifocal leukoencephalopathy after CAR-T therapy in a patient with refractory DLBCL

  森木朝子, 大東寛幸, 宮下直樹, 須藤啓斗, 日高大輔, 安本篤史, 後藤秀樹, 杉田純一, 小野澤真弘, 橋本大吾, 豊嶋崇徳  日本造血細胞移植学会総会プログラム・抄録集  43rd-  2021
• Fluid retention after allogeneic hematopoietic stem cell transplantation has a poor prognosis

  宮下直樹, 須藤啓斗, 日高大輔, 大東寛幸, 荒隆英, 白鳥聡一, 安本篤史, 後藤秀樹, 杉田純一, 小野澤真弘, 中川雅夫, 遠藤知之, 橋本大吾, 豊嶋崇徳  日本造血細胞移植学会総会プログラム・抄録集  43rd-  2021
• 急性GVHD・クローン病に対する羊膜由来間葉系幹細胞の医師主導治験 兵庫医科大学発・初認定ベンチャーによる開発をめざして

  山原 研一, 濱田 彰子, 大西 俊介, 相馬 俊裕, 岡本 里香, 中村 志郎, 岡田 昌也, 吉原 哲, 吉原 享子, 橋本 大吾, 磯江 敏幸, 豊嶋 崇徳, 佐藤 典宏, 藤盛 好啓  兵庫医科大学医学会雑誌  43-  (1)  41  -45  2018/09  [Not refereed][Not invited]
   

  我々は免疫調整作用を有する間葉系幹細胞(MSC)の中でも、(1)幹細胞数が多く、(2)増殖能も高く、(3)採取に侵襲性のない羊膜由来MSCに着目し、既存治療抵抗性の急性GVHDやクローン病といった難治性免疫関連疾患を対象とし、細胞治療研究を進めている。2017年、我々は世界で初めて羊膜MSCの治験製剤化に成功し、急性GVHDやクローン病に対する医師主導治験を開始し、現在は兵庫医科大学が羊膜MSCの治験製品(治験製品名:AM01)を提供し、兵庫医科大学病院・北海道大学病院を実施医療機関とした急性GVHD・クローン病に対する第I/II相医師主導治験を進めている。今後の更なる治験の加速化を目指し、兵庫医科大学発・初認定ベンチャーを立ちあげており、羊膜MSC AM01を再生医療等製品として早期の製造販売承認取得を目指す。(著者抄録)
• AMLにおけるWT1発現量と染色体・遺伝子異常の関連

  日高 大輔, 小野澤 真弘, 橋口 淳一, 宮下 直洋, 笠原 耕平, 藤澤 真一, 早瀬 英子, 岡田 耕平, 白鳥 聡一, 後藤 秀樹, 杉田 純一, 中川 雅夫, 加畑 馨, 橋本 大吾, 遠藤 知之, 山本 聡, 堤 豊, 長谷山 美仁, 永嶋 貴博, 盛 暁生, 太田 秀一, 酒井 基, 石原 敏道, 今井 陽俊, 宮城島 拓人, 柿木 康孝, 黒澤 光俊, 小林 一, 岩崎 博, 清水 力, 近藤 健, 豊嶋 崇徳  臨床血液  59-  (7)  964  -964  2018/07  [Not refereed][Not invited]
  
• Cell therapy for acute GVHD using human amnion-derived MSC

  山原 研一, 濵田 彰子, 大西 俊介, 黒田 将子, 相馬 俊裕, 岡本 里香, 岡田 昌也, 吉原 哲, 吉原 享子, 橋本 大吾, 磯江 敏幸, 豊嶋 崇徳, 佐藤 典宏, 小川 啓恭, 藤盛 好啓  臨床免疫・アレルギー科 = Clinical immunology & allergology  70-  (1)  18  -24  2018/07  [Not refereed][Not invited]
  
• 羊膜間葉系幹細胞の細胞製剤化と急性GVHDに対する第I/II相医師主導治験

  山原研一, 浜田彰子, 黒田将子, 岡田昌也, 岡田昌也, 吉原享子, 吉原哲, 相馬俊裕, 橋本大吾, 佐藤典宏, 豊嶋崇徳, 小川啓恭, 藤盛好啓  日本輸血細胞治療学会誌  64-  (2)  451  -451  2018/04/23  [Not refereed][Not invited]
  
• ステロイド抵抗性急性移植片対宿主病に対するヒト間葉系幹細胞療法の後方視的解析

  白鳥 聡一, 早瀬 英子, 岡田 耕平, 後藤 秀樹, 杉田 純一, 小野澤 真弘, 中川 雅夫, 加畑 馨, 橋本 大吾, 遠藤 知之, 近藤 健, 豊嶋 崇徳  日本輸血細胞治療学会誌  64-  (2)  452  -452  2018/04  [Not refereed][Not invited]
  
• FUNCTIONAL COMPARISON BETWEEN Spectra Optia^® MNC AND CMNC MODES FOR PERIPHERAL BLOOD STEM CELL COLLECTION

  Ito Makoto, Takahashi Syuichiro, Miyashita Naohiro, Goto Hideki, Onozawa Masahiro, Shiratori Souichi, Sugita Junichi, Hashimoto Daigo, Akizawa Koji, Sato Norihiro, Teshima Takanori, Hayase Eiko, Watanabe Chiaki, Uwatoko Takayo, Uozumi Ryo, Hayashi Yasuhiro, Hayasaka Koji, Mogi Yuko, Kahata Kaoru  Japanese Journal of Transfusion and Cell Therapy  64-  (6)  742  -751  2018  [Not refereed][Not invited]
   

  <p><b>Background: </b>Spectra Optia^® is an apheresis system that enables peripheral blood stem cell collection (PBSCC) to be easily conducted due to its unique automated interface management system. We retrospectively analyzed the number for CD34-positive cells in collected products and the collection efficiency for CD34-positive cells between the Spectra Optia^® MNC mode (MNC group) and CMNC mode (CMNC group) for PBSCC.</p><p><b>Methods: </b>We retrospectively analyzed 233 cases of PBSCC (autologous PBSCC: 103 cases, allogeneic PBSCC: 130 cases), which were performed in our institution between August 2013 and February 2018.</p><p><b>Results: </b>In autologous PBSCC, there was no significant difference in the number of CD34-positive cells in collected products or the collection efficiency for CD34-positive cells between the two groups. In allogeneic PBSCC, the number of CD34-positive cells in collected products and the collection efficiency for CD34-positive cells in the CMNC group were significantly higher than those in the MNC group. Peripheral blood platelet count and hemoglobin concentration were identified as the factors influencing the collection efficiency for CD34-positive cells.</p><p><b>Conclusion: </b>In autologous PBSCC, the number and collection efficiency for CD34-positive cells were not significantly different between the two modes, whereas in allogeneic PBSCC, the CMNC mode was more efficient for PBSCC than the MNC mode.</p>
• 末梢血幹細胞採取におけるCD34陽性細胞採取効率不良であった血小板数高値の症例

  伊藤誠, 早瀬英子, 早瀬英子, 渡邊千秋, 上床貴代, 魚住諒, 林泰弘, 砂後谷華奈, 道又理恵, 早坂光司, 茂木祐子, 加畑馨, 加畑馨, 橋本大吾, 佐藤典宏, 豊嶋崇徳, 清水力  日本造血細胞移植学会総会プログラム・抄録集  40th-  256  2017/12/11  [Not refereed][Not invited]
  
• HEMATOLOGICAL MALIGNANCIES IN SOLID ORGAN TRANSPLANT RECIPIENTS: RETROSPECTIVE SINGLE-CENTER ANALYSIS IN JAPAN

  K. Fujimoto, I. Daiki, R. Goto, K. Morita, T. Ooka, K. Hatanaka, H. Goto, J. Sugita, M. Onozawa, D. Hashimoto, K. Kahata, T. Kondo, Y. Matsuno, T. Shimamura, T. Teshima  HAEMATOLOGICA  102-  693  -693  2017/06  [Not refereed][Not invited]
  
• IMATINIB VS. DASATINIB FOR OUTCOMES AFTER ALLOGENEIC STEM CELL TRANSPLANTATION FOR PATIENTS WITH PH plus ACUTE LYMPHOBLASTIC LEUKEMIA

  A. Shigematsu, S. Ota, H. Goto, K. Minauchi, J. Sugita, D. Hashimoto, M. Obara, T. Endo, M. Imamura, T. Teshima, N. Kobayashi  HAEMATOLOGICA  102-  354  -354  2017/06  [Not refereed][Not invited]
  
• 当院においてドナーリンパ球輸注を施行した34症例の検討

  石尾 崇, 立野 貴大, 笠原 耕平, 小杉 瑞葉, 白鳥 聡一, 岡田 耕平, 後藤 秀樹, 杉田 純一, 小野澤 真弘, 橋本 大吾, 加畑 馨, 藤本 勝也, 遠藤 知之, 近藤 健, 豊嶋 崇徳  日本輸血細胞治療学会誌  63-  (2)  148  -149  2017/04  [Not refereed][Not invited]
  
• Vitamin A-Coupled Liposomes Carrying siRNA Against HSP47 Ameliorate Skin Fibrosis in Chronic Graft-Versus-Host Disease

  Tomohiro Yamakawa, Daigo Hashimoto, Eiko Hayase, Shuichiro Takahashi, Takanori Teshima  BLOOD  128-  (22)  2016/12  [Not refereed][Not invited]
  
• 胆嚢炎症状を契機に発症したTAFRO症候群

  関根 隆博, 後藤 秀樹, 日高 大輔, 早瀬 英子, 小杉 瑞葉, 岡田 耕平, 白鳥 総一郎, 杉田 純一, 小野澤 真弘, 橋本 大吾, 加畑 馨, 藤本 勝也, 遠藤 知之, 近藤 健, 豊嶋 崇徳  臨床血液  57-  (12)  2608  -2608  2016/12  [Not refereed][Not invited]
  
• HIV感染症合併血友病患者に対するMRIによる脳スクリーニングの意義

  遠藤知之, 遠藤知之, 宮下直洋, 宮下直洋, 笠原耕平, 笠原耕平, 小杉瑞葉, 岡田耕平, 白鳥聡一, 後藤秀樹, 杉田純一, 小野澤真弘, 橋本大吾, 加畑馨, 藤本勝也, 藤本勝也, 近藤健, 橋野聡, 橋野聡, 豊嶋崇徳, 豊嶋崇徳  日本エイズ学会誌  18-  (4)  439  -439  2016/11/20  [Not refereed][Not invited]
  
• 肺胞蛋白症を合併し致死的な経過を辿った骨髄異形成症候群の1例

  大東 寛幸, 松川 敏大, 金谷 穣, 後藤 秀樹, 橋本 大吾, 加畑 馨, 遠藤 知之, 田中 伸哉, 豊嶋 崇徳  臨床血液  57-  (11)  2398  -2398  2016/11  [Not refereed][Not invited]
  
• HIV感染症合併血友病患者に対するMRIによる脳スクリーニングの意義

  遠藤 知之, 宮下 直洋, 笠原 耕平, 小杉 瑞葉, 岡田 耕平, 白鳥 聡一, 後藤 秀樹, 杉田 純一, 小野澤 真弘, 橋本 大吾, 加畑 馨, 藤本 勝也, 近藤 健, 橋野 聡, 豊嶋 崇徳  日本エイズ学会誌  18-  (4)  439  -439  2016/11  [Not refereed][Not invited]
  
• 当院における同種末梢血幹細胞採取の検討

  杉田 純一, 大東 寛幸, 橋口 淳一, 松川 敏大, 金谷 穣, 小杉 瑞葉, 松岡 里湖, 後藤 秀樹, 小野澤 真弘, 橋本 大吾, 加畑 馨, 藤本 勝也, 遠藤 知之, 近藤 健, 豊嶋 崇徳  日本輸血細胞治療学会誌  62-  (3)  490  -490  2016/06  [Not refereed][Not invited]
  
• Spectra Optiaによる末梢血幹細胞採取の検討

  伊藤 誠, 加畑 馨, 渡邊 千秋, 上床 貴代, 米岡 麻記, 茂木 祐子, 成田 玲子, 魚住 諒, 石岡 聡子, 早坂 光司, 渋谷 斉, 小杉 瑞葉, 重松 明男, 高橋 正二郎, 杉田 純一, 橋本 大吾, 佐藤 典宏, 豊嶋 崇徳, 清水 力  日本輸血細胞治療学会誌  62-  (3)  490  -490  2016/06  [Not refereed][Not invited]
  
• 当院における骨髄腫患者からの末梢血幹細胞動員効率の検討

  加畑馨, 加畑馨, 伊藤誠, 渡邊千秋, 上床貴代, 米岡麻記, 小杉瑞葉, 小杉瑞葉, 重松明男, 重松明男, 高橋正二郎, 高橋正二郎, 杉田純一, 橋本大吾, 山本聡, 佐藤典宏, 清水力, 豊嶋崇徳  日本輸血細胞治療学会誌  62-  (2)  402  -402  2016/04/01  [Not refereed][Not invited]
  
• 当院におけるSpectraとOptia 2モードの使用経験

  伊藤 誠, 加畑 馨, 渡邊 千秋, 上床 貴代, 米岡 麻記, 小杉 瑞葉, 重松 明男, 高橋 正二郎, 杉田 純一, 橋本 大吾, 佐藤 典宏, 豊嶋 崇徳, 清水 力  日本輸血細胞治療学会誌  62-  (2)  299  -299  2016/04  [Not refereed][Not invited]
  
• Molecular mechanism of graft-versus-host disease and molecular targeted therapy

  高橋 秀一郎, 橋本 大吾, 豊嶋 宗徳  血液内科 = Hematology  72-  (3)  330  -336  2016/03
• Topical Ruxolitinib Protects LGR5+Stem Cells in the Hair Follicle and Ameliorates Skin Graft-Versus-Host Disease

  Shuichiro Takahashi, Daigo Hashimoto, Eiko Hayase, Takanori Teshima  BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION  22-  (3)  S21  -S22  2016/03  [Not refereed][Not invited]
  
• The role of fungal infections in acute graft-versus-host disease

  橋本 大吾, 瓜生 英尚, 豊嶋 崇徳  血液内科 = Hematology  71-  (6)  775  -780  2015/12
• R-spondin1 Promotes Paneth Cell Growth, Maintains Intestinal Microbial Ecology, and Ameliorates GvHD

  Eiko Hayase, Daigo Hashimoto, Kiminori Nakamura, Yoshitoshi Ogura, Tetsuya Hayashi, Ken Kurokawa, Tokiyoshi Ayabe, Takanori Teshima  BLOOD  126-  (23)  2015/12  [Not refereed][Not invited]
  
• 初回ART導入におけるRaltegravirとDolutegravirの血液毒性への関与

  後藤秀樹, 後藤秀樹, 遠藤知之, 藤本勝也, 近藤健, 加畑馨, 橋本大吾, 小野澤真弘, 杉田純一, 松川敏大, 笠原耕平, 宮下直洋, 橋野聡, 佐藤典宏, 豊嶋崇徳  日本エイズ学会誌  17-  (4)  510  -510  2015/11/20  [Not refereed][Not invited]
  
• Cardio-ankle vascular index(CAVI)を用いたHIV感染者の動脈硬化の評価とリスク因子の検討

  遠藤 知之, 宮下 直洋, 笠原 耕平, 渡部 恵子, 武内 阿味, 松川 敏大, 金谷 穣, 小杉 瑞葉, 松岡 里湖, 後藤 秀樹, 杉田 純一, 小野澤 真弘, 橋本 大吾, 加畑 馨, 藤本 勝也, 近藤 健, 橋野 聡, 豊嶋 崇徳  日本エイズ学会誌  17-  (4)  392  -392  2015/11  [Not refereed][Not invited]
  
• IDENTIFICATION OF FIP1L1-PDGFRA ASSOCIATING MOLECULE THAT LOCATES IN THE NUCLEUS AND AUGMENTS THE ACTIVITY OF FIP1L1-PDGFRA

  T. Kondo, M. Ibata, J. Iwasaki, Y. Fujioka, K. Nakagawa, S. Darmanin, M. Onozawa, D. Hashimoto, Y. Ohba, S. Hatakeyama, T. Teshima  HAEMATOLOGICA  100-  327  -327  2015/06  [Not refereed][Not invited]
  
• Graft-Versus-Host Disease Targets Granulosa Cell of Ovarian Follicle and Causes Infertility after Allogeneic Hematopoietic Stem Cell Transplantation

  Sonoko Shimoji, Daigo Hashimoto, Koji Kato, Hidetsugu Tujigiwa, Koichi Akashi, Takanori Teshima  BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION  21-  (2)  S26  -S27  2015/02  [Not refereed][Not invited]
  
• 顆粒球採取におけるSpectra Optiaの採取効率ならびにドナーへの影響

  岡田耕平, 杉田純一, 伊藤誠, 米岡麻記, 櫻澤貴代, 渡邊千秋, 橋本大吾, 重松明男, 佐藤典宏, 清水力, 豊嶋崇徳  日本輸血細胞治療学会誌  60-  (2)  409  -409  2014/04/10  [Not refereed][Not invited]
  
• Immunology of graft-versus-host disease : blockade of lymphocyte chemotaxis

  橋本 大吾  細胞  45-  (11)  512  -515  2013/10
• Therapeutic efficacy of antitumor monoclonal antibodies combined with chemotherapy depends on innate immunity and NK1.1-innate lymphoid cells.

  Marina Moskalenko, Michael Pan, Daigo Hashimoto, Arthur Mortha, Sebastian G. Bernardo, Marylene Leboeuf, Alan Houghton, Jedd Wolchok, Steven Burakoff, Miriam Merad, Yvonne M. Saenger  CANCER RESEARCH  73-  2013/01  [Not refereed][Not invited]
  
• CD169(+) Macrophages Regulate Erythropoiesis Under Homeostasis, Recovery From Erythron Injury and in JAK2(V617F)-Induced Polycythemia Vera

  Andrew Chow, Matthew Huggins, Jalal Ahmed, Daniel Lucas, Daigo Hashimoto, Yuya Kunisaki, Sandra Pinho, Marylene Leboeuef, Clara Noizat, Nico van Rooijen, Masato Tanaka, Zlizhuang Joe Zhao, Aviv Bergman, Miriam Merad, Paul S. Frenette  BLOOD  120-  (21)  2012/11  [Not refereed][Not invited]
  
• Dendritic Cell Derived C3a/C5a Mediate Murine Graft Versus Host Disease.

  W. -H Kwan, D. Hashimoto, E. Paz-Artal, K. Ostrow, M. Greter, M. Merad, P. S. Heeger  AMERICAN JOURNAL OF TRANSPLANTATION  11-  152  -152  2011/04  [Not refereed][Not invited]
  
• Anti-tyrosinase related protein 1 (TRP1) antibody combined with cyclophosphamide induces adaptive immunity against melanoma

  Yvonne M. Saenger, Michael Pan, Daigo Hashimoto, Bradley Glodny, Shaily Shah, Alan N. Houghton, Taha Merghoub, Jedd D. Wolchok, Miriam Merad  CANCER RESEARCH  71-  2011/04  [Not refereed][Not invited]
  
• Pre-Transplant CSF-1 Therapy Expands the Recipient Macrophage Pool and Modulates Graft Versus Host Disease After Allogeneic Hematopoietic Cell Transplantation

  Daigo Hashimoto, Andrew Chow, Melanie Greter, Marylene Leboeuf, Florent Ginhoux, Takanori Teshima, Miriam Merad  BLOOD  116-  (21)  112  -112  2010/11  [Not refereed][Not invited]
  
• Protection of the Intestinal Epithelium from Conditioning with R-spondin1 Ameliorates Graft-Versus-Host Disease

  Shuichiro Takashima, Kazutoshi Aoyama, Motoko Koyama, Daigo Hashimoto, Takeshi Oshima, Kazuma Tomizuka, Koichi Akashi, Takanori Teshima  BLOOD  112-  (11)  32  -32  2008/11  [Not refereed][Not invited]
  
• Host plasmacytoid or conventional dendritic cells alone are sufficient to initiate graft-versus-host disease

  Motoko Koyama, Daigo Hashimoto, Kazutoshi Aoyama, Ken-ichi Matuoka, Kennosuke Karube, Kiyoshi Takeda, Koichi Ohshima, Koichi Akashi, Mitsune Tanimoto, Mine Harada, Takanori Teshima  BLOOD  110-  (11)  643A  -644A  2007/11  [Not refereed][Not invited]
  
• Alloantigens expression on host non-hematopoietic cells leads to donor T cell exhaustion and reduces GVL effects

  D. Hashimoto, S. Asakura, K. -I. Matsuoka, Y. Sakoda, M. Koyama, K. Aoyama, M. Tanimoto, T. Teshima  BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION  13-  (2)  108  -108  2007/02  [Not refereed][Not invited]
  
• Donor-reactive thymic-dependent Th1 cells cause chronic GVHD

  Y. Sakoda, D. Hashimoto, S. Asakura, K. Takeuchi, M. Harada, M. Tanimoto, T. Teshima  BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION  13-  (2)  16  -16  2007/02  [Not refereed][Not invited]
  
• Early recovery of host T cells predicts primary graft rejection following non-myeloablative conditioning allogeneic hematopoietic stem cell transplantation

  M. Koyama, D. Hashimoto, K. Kamezaki, A. Numata, Y. Sakoda, K. Aoyama, K. Takenaka, T. Miyamoto, N. Harada, K. Nagafuji, K. Akashi, M. Tanimoto, M. Harada, T. Teshima  BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION  13-  (2)  127  -127  2007/02  [Not refereed][Not invited]
  
• Homeostatic proliferation of donor T cells reduces their capacity for inducing acute graft-versus-host disease.

  Y Maeda, T Teshima, D Hashimoto, M Tammoto, P Reddy  BLOOD  106-  (11)  378A  -378A  2005/11  [Not refereed][Not invited]
  
• Impaired thymic negative selection causes chronic graft-versus-host disease after allogeneic bone marrow transplantation.

  Y Sakoda, D Hashimoto, K Takeuchi, S Asakura, K Akashi, M Tanimoto, M Harada, T Teshima  BLOOD  106-  (11)  137A  -137A  2005/11  [Not refereed][Not invited]
  
• Fetal tolerance to maternal antigens improves the outcome of allogeneic bone marrow transplantation by a CD4+CD25+T cell-dependent mechanism.

  KI Matsuoka, T Ichinohe, S Asakura, D Hashimoto, M Tanimoto, T Teshima  BLOOD  106-  (11)  136A  -136A  2005/11  [Not refereed][Not invited]
  
• FTY720-induced sequestration of donor T cells in lymph nodes leads to activation-induced apoptosis of alloreactive T cells and reduced graft-versus-host disease.

  D Hashimoto, S Asakura, K Matsuoka, Y Sakoda, M Tanimoto, T Teshima  BLOOD  104-  (11)  836A  -836A  2004/11  [Not refereed][Not invited]
  
• Alloantigen expression on host target epithelium inhibits graft-versus-leukemia (GVL) effects.

  S Asakura, D Hashimoto, K Matsuoka, Y Sakoda, M Tanimoto, T Teshima  BLOOD  104-  (11)  172A  -172A  2004/11  [Not refereed][Not invited]
  
• Host NKT cells promote Th2 polarization of donor T cells and regulate acute GVHD after experimental BMT via a STAT6-dependent mechanism.

  D Hashimoto, S Asakura, S Miyake, T Yamamura, L Van Kaer, M Tanimoto, T Teshima  BLOOD  102-  (11)  191A  -192A  2003/11  [Not refereed][Not invited]
  
• Fournier's gangrene after unrelated cord blood stem cell transplantation.

  C Yoshida, K Kojima, K Shinagawa, D Hashimoto, S Asakura, S Takata, M Tanimoto  Annals of hematology  81-  (9)  538  -9  2002/09  [Refereed][Not invited]
   

  A 16-year-old boy with refractory acute myelogenous leukemia developed Fournier's gangrene as an early complication after two-antigen HLA-mismatched unrelated cord blood stem cell transplantation. On day 25 after the transplantation, he noted abrupt onset of penile swelling with miction pain. The penile inflammation rapidly extended posteriorly to involve the scrotum and perianal tissues, inferiorly to involve the thighs, and superiorly up the lower abdominal region within the next 36 h, and he died from sepsis on day 27. Fournier's gangrene presenting as a genitoperineal necrotizing fasciitis should be considered as a potential complication in umbilical-cord blood recipients in the cytopenic post-transplant phase.
• Dose-finding phase I study of simultaneous weekly infusion with doxorubicin and docetaxel in patients with advanced breast cancer.

  Y Ito, K Aiba, N Horikoshi, T Saotome, T Irie, K Sugiyama, M Nakane, D Hashimoto, N Yoshida, N Mizunuma, S Takahashi, Y Tanigawara  International journal of clinical oncology  6-  (5)  242  -7  2001/10  [Refereed][Not invited]
   

  BACKGROUND: Combination therapy with doxorubicin (DOX) and docetaxel (DOC), given 3 weeks apart, is one of the standard regimens used for treating metastatic breast cancer, but it frequently generates febrile neutropenia. To find a safer regimen with less myelotoxicity and the appropriate dose intensity, we conducted a phase I study of simultaneous weekly infusion with DOX and DOC. METHODS: Twenty-five patients with advanced breast cancer were treated with an intravenous push-injection of DOX that was immediately followed by a 1-h infusion of DOC. This was repeated every week for at least 6 weeks. The premedication employed was three 4-mg doses of dexamethasone every week. Patients were divided into four groups for which the doses of DOX and DOC were escalated in 5-mg/m2 increments. RESULTS: In the 18 patients who were treated with DOX 15 or 20 mg/m2 and DOC 25 mg/m2, or lower, the regimen was found to be tolerable, without febrile episodes. The regimen with 20 mg/m2 of DOX and 30 mg/m2 of DOC was the maximum tolerated dose. Other indications of grade 3 toxicity included asthenia in 4% of patients, anorexia in 8%, and vomiting in 8%. Of the 25 patients, 14 had a partial response. The overall response rate was 56% (95% confidence interval [CI], 35% to 77%). The recommended dose for further trial was 20 mg/m2 of DOX and 25 mg/m2 of DOC. CONCLUSION: Simultaneous weekly infusion with DOX and DOC was feasible, with modest neutropenia and preserved dose intensity. This regimen may be helpful in the management of patients with advanced breast cancer.

Books etc

• 専門医のための血液病学

  橋本 大吾 (Contributor4. 免疫担当細胞とその分化機構 1)自然免疫, 5. 造血幹細胞移植 4)GVHD)
  医学書院 2021/12
• 造血細胞移植看護基礎テキスト

  日本造血・免疫細胞療法学会 (Contributor第1章造血幹細胞移植の基礎知識 4. 移植免疫)
  南江堂 2021/06 (ISBN: 9784524228270) vii, 234p
• EBM血液疾患の治療〈2019‐2020〉

  押味, 和夫, 金倉, 譲, 木崎, 昌弘, 鈴木, 律朗, 神田, 善伸 (Contributor腸内細菌が同種移植後の経過に及ぼす影響 P525-531)
  中外医学社 2019/11 (ISBN: 4498125126) 冊
• みんなに役立つGVHD(移植片対宿主病)の基礎と臨床

  豊嶋, 崇徳 (Contributor自然免疫とGVHD p86-90)
  医薬ジャーナル社 2013/08 (ISBN: 9784753226320) 423p

Association Memberships

• The American Society of Hematology   THE JAPAN SOCIETY OF TRANSFUSION MEDICINE AND CELL THERAPY   Japan Society for Hematopoietic Stem Cell Transplantation   The JAPANESE SOCIETY OF HEMATOLOGY   

Research Projects

• Liver organoid-based study of macrophage-induced injury of liver stem cells in GVHD

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2021/04 -2024/03 

  Author : 橋本 大吾

   

  マウス同種造血幹細胞移植を用いた肝臓GVHDモデルを確立した。病理学的検討では, 肝臓GVHDの主たる標的は胆管上皮であることが確認された。胆管周囲にT細胞やマクロファージが浸潤しており, 胆管上皮のアポトーシス (cleaved caspase-3発現)や, 黄疸の発症を伴っていた。肝障害発症後のday21に, LGR5陽性肝臓組織幹細胞が増加し, その後減少することを発見した。次に胆管上皮幹細胞の動態を明らかにすることを目指し, 肝臓右葉から胆管上皮を単離し, そこから得られる胆管上皮オルガノイドの定量を行い, 胆管上皮幹細胞の量的変化を観察する系を確立した。この系を用いた検討で, 同種造血幹細胞移植後の肝臓GVHDが発症した後の移植後day21に胆管上皮幹細胞が増加し, その後急速に減少することが判明した。これは, 肝臓GVHDによる胆管上皮傷害を修復するために, 幹細胞の活性化と増殖が生じるものの, それらの幹細胞もGVHDの標的となって修復が行われなくなることを示している。
• Development of a novel chronic GVHD therapy targeting macrophage-myofibroblast axis

  Grants-in-Aid for Scientific Research：基盤研究(C)

  Date (from‐to) : 2017/04 -2020/03 

  Author : Daigo Hashimoto
• Reconstitution of phagocyte system after hematopoietic stem cell transplantation

  Grants-in-Aid for Scientific Research：基盤研究(C)

  Date (from‐to) : 2014/04 -2017/03 

  Author : Daigo Hashimoto
• PD-1/PD-L1経路を利用した臓器特異的GVHD予防法の開発

  日本学術振興会：科学研究費助成事業

  Date (from‐to) : 2008 -2010 

  Author : 橋本 大吾

   

  PD-L1をLangerin promoter下に導入し皮膚Langerhans細胞に特異的にPD-L1を高発現させ、皮膚に特異的な免疫抑制を達成しようと考えた。しかしLangerin陽性細胞は脾臓、リンパ節、肝臓、肺などを含めた多臓器に発現し、これらの細胞にPD-L1を高発現させると広範で持続的な免疫不全を招くおそれがあることがわかった。そこでもともとPD-L1を高発現する細胞を利用して移植片対宿主病(GVHD)予防を達成することを考えた。PD-L1は抗原提示細胞および炎症環境下における非血液細胞を中心に発現していることが知られていたが、これらの細胞の中でもマクロファージ、CD11b陽性樹状細胞。Gr1^ MonocyteのPD-L1発現はCD8陽性樹状細胞、B細胞、Gr1^ Monocyteに比較して高いことがわかった。PD-L1を高発現するGr1^ MonocyteやマクロファージはT細胞の活性化・増殖を抑制しGVHDの発症を抑制していることがわかった。FAS依存性アポトーシスをM-CSFR陽性細胞に誘導できるマウス(MaFIA)を利用してレシピエントからこれらの細胞を除去するとGVHDが増悪した。逆に純化したGr1^ Monocyteを輸注することによってGVHD予防が強化された。一方PD-L1の発現が低いGr1^ MonOcyteを輸注してもGVHDの重症度は変わらなかった。またM-CSFを移植前に投与することによってレシピエントのマクロファージおよびMonocyteを増殖させることができ、GVHDが抑制されることがわかった。臓器別の免疫抑制という目標は臓器別にこのような細胞の増殖を誘導する、もしくはこれらの細胞を局所的に輸注することによって達成しうると考えられる。
• Separation of GVHD and GVL by NKT cell stimulation

  Grants-in-Aid for Scientific Research：若手研究(B)

  Date (from‐to) : 2006/04 -2007/03 

  Author : Daigo Hashimoto