清野 研一郎 (セイノ ケンイチロウ)
| 遺伝子病制御研究所 病態研究部門 | 教授 |
Last Updated :2025/06/07
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- Amelioration of liver fibrosis with autologous macrophages induced by IL-34-based condition.
Yuichi Igarashi, Haruka Wada, Masato Muto, Ryohei Sone, Yoshinori Hasegawa, Ken-Ichiro Seino
Inflammation and regeneration, 45, 1, 2, 2, 2025年01月24日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: For the treatment of liver fibrosis, several novel cell therapies have been proposed. Autologous macrophage therapy has been reported as one of the promising treatments. So far, most studies have used colony-stimulating factor 1 (CSF-1) to induce the differentiation of macrophage progenitor cells. The receptor for CSF-1, CSF-1R possesses another ligand, interleukin 34. However, the therapeutic capacity for liver fibrosis by interleukin 34-induced macrophages has not been evaluated. METHODS: We have employed acute (bile duct ligation) and chronic (administration of carbon tetrachloride or thioacetamide) liver fibrosis models. Using these models, we evaluated the therapeutic capacity of macrophages induced by interleukin 34-based conditions. In most experiments, interleukin 4 was also added to the differentiation process to induce alternative-activated macrophages. As a mechanism analysis, we have examined liver inflammation and damage, the status of stellate cells, and the immunosuppressive capacity of the macrophages. Human macrophages were differentiated from CD14+ monocytes and analyzed. RESULTS: In both acute and chronic liver damage experiments, interleukin 34-induced macrophages significantly ameliorated liver fibrosis. The addition of interleukin 4 to the differentiation process resulted in an increase of obtained macrophages and a bias to alternative activated macrophages (so-called M2). The alternative activated macrophages (M2-type) showed a reproducible therapeutic effect of liver fibrosis with a suppression of parameters of liver inflammation and damage, stellate cells, and T cell activation. Similar macrophages could be differentiated from human CD14+ monocytes in the presence of interleukin 34 plus interleukin 4, and a therapeutic effect was observed using a humanized mouse model. CONCLUSIONS: Interleukin 34-induced macrophages, particularly when additionally stimulated with interleukin 4, significantly ameliorated the liver fibrosis. - Tumor cell-induced macrophage senescence plays a pivotal role in tumor initiation followed by stable growth in immunocompetent condition.
Haruka Wada, Ryo Otsuka, Wilfred T V Germeraad, Tomoki Murata, Toru Kondo, Ken-Ichiro Seino
Journal for immunotherapy of cancer, 11, 11, 2023年11月, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The cancer stem cell theory proposes that tumor formation in vivo is driven only by specific tumor-initiating cells having stemness; however, clinical trials conducted to test drugs that target the tumor stemness provided unsatisfactory results thus far. Recent studies showed clear involvement of immunity in tumors; however, the requirements of tumor-initiation followed by stable growth in immunocompetent individuals remain largely unknown. METHODS: To clarify this, we used two similarly induced glioblastoma lines, 8B and 9G. They were both established by overexpression of an oncogenic H-RasL61 in p53-deficient neural stem cells. In immunocompromised animals in an orthotopic transplantation model using 1000 cells, both show tumor-forming potential. On the other hand, although in immunocompetent animals, 8B shows similar tumor-forming potential but that of 9G's are very poor. This suggests that 8B cells are tumor-initiating cells in immunocompetent animals. Therefore, we hypothesized that the differences in the interaction properties of 8B and 9G with immune cells could be used to identify the factors responsible for its tumor forming potential in immunocompetent animals and performed analysis. RESULTS: Different from 9G, 8B cells induced senescence-like state of macrophages around tumors. We investigated the senescence-inducing factor of macrophages by 8B cells and found that it was interleukin 6. Such senescence-like macrophages produced Arginase-1, an immunosuppressive molecule known to contribute to T-cell hyporesponsiveness. The senescence-like macrophages highly expressed CD38, a nicotinamide adenine dinucleotide (NAD) glycohydrolase associated with NAD shortage in senescent cells. The addition of nicotinamide mononucleotide (NMN), an NAD precursor, in vitro inhibited to the induction of macrophage senescence-like phenotype and inhibited Arginase-1 expression resulting in retaining T-cell function. Moreover, exogenous in vivo administration of NMN after tumor inoculation inhibited tumor-initiation followed by stable growth in the immunocompetent mouse tumor model. CONCLUSIONS: We identified one of the requirements for tumor-initiating cells in immunocompetent animals. In addition, we have shown that tumor growth can be inhibited by externally administered NMN against macrophage senescence-like state that occurs in the very early stages of tumor-initiating cell development. This therapy targeting the immunosuppressive environment formed by macrophage senescence-like state is expected to be a novel promising cancer therapeutic strategy. - Induced pluripotent stem cell-derived hematopoietic stem and progenitor cells induce mixed chimerism and donor-specific allograft tolerance.
Tomoki Murata, Naoki Hama, Tomoki Kamatani, Akihiro Mori, Ryo Otsuka, Haruka Wada, Ken-Ichiro Seino
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, 23, 9, 1331, 1344, 2023年09月, ［国際誌］
英語, 研究論文（学術雑誌）, In transplantation using allogeneic induced pluripotent stem cells (iPSCs), strategies focused on major histocompatibility complexes were adopted to avoid immune rejection. We showed that minor antigen mismatches are a risk factor for graft rejection, indicating that immune regulation remains one of the most important issues. In organ transplantation, it has been known that mixed chimerism using donor-derived hematopoietic stem/progenitor cells (HSPCs) can induce donor-specific tolerance. However, it is unclear whether iPSC-derived HSPCs (iHSPCs) can induce allograft tolerance. We showed that 2 hematopoietic transcription factors, Hoxb4 and Lhx2, can efficiently expand iHSPCs with a c-Kit+Sca-1+Lineage- phenotype, which possesses long-term hematopoietic repopulating potential. We also demonstrated that these iHSPCs can form hematopoietic chimeras in allogeneic recipients and induce allograft tolerance in murine skin and iPSC transplantation. With mechanistic analyses, both central and peripheral mechanisms were suggested. We demonstrated the basic concept of tolerance induction using iHSPCs in allogeneic iPSC-based transplantation. - Augmented interferon regulatory factor 7 axis in whole tumor cell vaccines prevents tumor recurrence by inducing interferon gamma-secreting B cells
Nabeel Kajihara, Yoshino Tanaka, Riko Takeuchi, Takuto Kobayashi, Masafumi Tanji, Tsukasa Ataka, Shiho Nakano, Taisho Yamada, Akinori Takaoka, Yoshinori Hasegawa, Ken-Ichiro Seino, Haruka Wada
OncoImmunology, 12, 1, Informa UK Limited, 2023年05月22日
研究論文（学術雑誌） - Induction of allograft tolerance by adoptive transfer of donor B cells: an immune regulatory strategy for transplantation using MHC-matched iPS cells.
Tomoki Murata, Ryo Otsuka, Airi Sasaki, Tomoki Kamatani, Haruka Wada, Hisashi Yamakawa, Yoshinori Hasegawa, Ken-Ichiro Seino
International immunology, 2023年04月13日, ［国際誌］
英語, 研究論文（学術雑誌）, For cellular or tissue transplantation using iPS cells (iPSCs), from the viewpoint of time and economic cost, an use of allogeneic ones is being considered. Immune regulation is one of the key issues in successful allogeneic transplantation. To reduce the risk of rejection, several attempts have been reported to eliminate effects of major histocompatibility complex (MHC) on the iPSCs-derived grafts. On the other hand, we have shown that minor antigen-induced rejection is not negligible even when the MHC's impact is mitigated. In organ transplantation, it is known that donor-specific blood transfusion (DST) can specifically control immune responses to the donor. However, whether DST could control the immune response in iPSC-based transplantation was not clarified. In this study, using a mouse skin transplantation model, we demonstrate that infusion of donor splenocytes can promote allograft tolerance in the MHC-matched but minor antigen-mismatched condition. When narrowing down the cell types, we found that infusion of isolated splenic B cells was sufficient to control rejection. As a mechanism, the administration of donor B cells induced unresponsiveness but not deletion in recipient T cells, suggesting that the tolerance was induced in the periphery. The donor B cell transfusion induced allogeneic iPSCs engraftment. These results suggest for the first time a possibility that DST using donor B cells could induce tolerance against allogeneic iPSC-derived grafts. - Interleukin-34 cancels anti-tumor immunity by PARP inhibitor.
Takayoshi Nakamura, Nabeel Kajihara, Naoki Hama, Takuto Kobayashi, Ryo Otsuka, Nanumi Han, Haruka Wada, Yoshinori Hasegawa, Nao Suzuki, Ken-Ichiro Seino
Journal of gynecologic oncology, 2022年12月21日, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVE: Breast cancer susceptibility gene 1 (BRCA1)-associated ovarian cancer patients have been treated with A poly (ADP-ribose) polymerase (PARP) inhibitor, extending the progression-free survival; however, they finally acquire therapeutic resistance. Interleukin (IL)-34 has been reported as a poor prognostic factor in several cancers, including ovarian cancer, and it contributes to the therapeutic resistance of chemotherapies. IL-34 may affect the therapeutic effect of PARP inhibitor through the regulation of tumor microenvironment (TME). METHODS: In this study, The Cancer Genome Atlas (TCGA) data set was used to evaluate the prognosis of IL-34 and human ovarian serous carcinoma. We also used CRISPR-Cas9 genome editing technology in a mouse model to evaluate the efficacy of PARP inhibitor therapy in the presence or absence of IL-34. RESULTS: We found that IL34 was an independent poor prognostic factor in ovarian serous carcinoma, and its high expression significantly shortens overall survival. Furthermore, in BRCA1-associated ovarian cancer, PARP inhibitor therapy contributes to anti-tumor immunity via the XCR1+ DC-CD8+ T cell axis, however, it is canceled by the presence of IL-34. CONCLUSION: These results suggest that tumor-derived IL-34 benefits tumors by creating an immunosuppressive TME and conferring PARP inhibitor therapeutic resistance. Thus, we showed the pathological effect of IL-34 and the need for it as a therapeutic target in ovarian cancer. - Tumor-derived interleukin-34 creates an immunosuppressive and chemoresistant tumor microenvironment by modulating myeloid-derived suppressor cells in triple-negative breast cancer.
Nabeel Kajihara, Takuto Kobayashi, Ryo Otsuka, Junko Nio-Kobayashi, Tomohiro Oshino, Masato Takahashi, Seiichi Imanishi, Ari Hashimoto, Haruka Wada, Ken-Ichiro Seino
Cancer immunology, immunotherapy : CII, 2022年09月14日, ［国際誌］
英語, 研究論文（学術雑誌）, Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype characterized by a lack of therapeutic targets. The paucity of effective treatment options motivated a number of studies to tackle this problem. Immunosuppressive cells infiltrated into the tumor microenvironment (TME) of TNBC are currently considered as candidates for new therapeutic targets. Myeloid-derived suppressor cells (MDSCs) have been reported to populate in the TME of TNBC, but their roles in the clinical and biological features of TNBC have not been clarified. This study identified that interleukin-34 (IL-34) released by TNBC cells is a crucial immunomodulator to regulate MDSCs accumulation in the TME. We provide evidence that IL-34 induces a differentiation of myeloid stem cells into monocytic MDSCs (M-MDSCs) that recruits regulatory T (Treg) cells, while suppressing a differentiation into polymorphonuclear MDSCs (PMN-MDSCs). As a result, the increase in M-MDSCs contributes to the creation of an immunosuppressive TME, and the decrease in PMN-MDSCs suppresses angiogenesis, leading to an acquisition of resistance to chemotherapy. Accordingly, blockade of M-MDSC differentiation with an estrogen receptor inhibitor or anti-IL-34 monoclonal antibody suppressed M-MDSCs accumulation causing retardation of tumor growth and restores chemosensitivity of the tumor by promoting PMN-MDSCs accumulation. This study demonstrates previously poorly understood mechanisms of MDSCs-mediated chemoresistance in the TME of TNBC, which is originated from the existence of IL-34, suggesting a new rationale for TNBC treatment. - Evaluation of immunosuppression protocols for MHC-matched allogeneic iPS cell-based transplantation using a mouse skin transplantation model.
Tomoki Kamatani, Ryo Otsuka, Tomoki Murata, Haruka Wada, Takeshi Takahashi, Akihiro Mori, Soichiro Murata, Hideki Taniguchi, Ken-Ichiro Seino
Inflammation and regeneration, 42, 1, 4, 4, 2022年02月02日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Off-the-shelf major histocompatibility complex (MHC)-matched iPS cells (iPSC) can potentially initiate host immune responses because of the existence of numerous minor antigens. To suppress allo-immune responses, combination of immunosuppressants is usually used, but its efficacy to the allogeneic iPSC-based transplantation has not been precisely evaluated. METHODS: Three transplantation models were used in this study; MHC-matched, minor antigen-mismatched mouse skin or iPSC-graft transplantation, and fully allogeneic human iPSC-derived liver organoid transplantation in immune-humanized mice. The recipients were treated with triple drugs combination (TDC; tacrolimus, methylprednisolone, and mycophenolate mofetil) or co-stimulatory molecule blockade (CB) therapy with some modifications. Graft survival as well as anti-donor T and B cell responses was analyzed. RESULTS: In the mouse skin transplantation model, immunological rejection caused by the minor antigen-mismatch ranged from mild to severe according to the donor-recipient combination. The TDC treatment could apparently control the mild skin graft rejection when combined with a transient T cell depletion, but unexpected anti-donor T or B cell response was observed. On the other hand, CB therapy, particularly when combined with rapamycin treatment, was capable of attenuating both mild and severe skin graft rejection and allowing them to survive long-term without any unfavorable anti-donor immune responses. The efficacy of the CB therapy was confirmed in both mouse and human iPSC-derived graft transplantation. CONCLUSIONS: The findings suggest that the CB-based treatment seems suitable to well manage the MHC-matched allogeneic iPSC-based transplantation. The TDC-based treatment may be also used to suppress the rejection, but screening of its severity prior to the transplantation seems to be needed. - Erratum: Interleukin-34 Limits the Therapeutic Effects of Immune Checkpoint Blockade.
Naoki Hama, Takuto Kobayashi, Nanumi Han, Fumihito Kitagawa, Nabeel Kajihara, Ryo Otsuka, Haruka Wada, Hee-Kyung Lee, Hwanseok Rhee, Yoshinori Hasegawa, Hideo Yagita, Muhammad Baghdadi, Ken-Ichiro Seino
iScience, 25, 1, 103713, 103713, 2022年01月21日, ［国際誌］
英語, [This corrects the article DOI: 10.1016/j.isci.2020.101584.]. - Macrophage-like iPS-derived Suppressor Cells Reduce Th1-mediated Immune Response to a Retinal Antigen.
Keitaro Hase, Kenichi Namba, Haruka Wada, Hyuma Tsuji, Aoi Maeda, Tomoki Murata, Ryo Otsuka, Daiju Iwata, Atsuhiro Kanda, Kousuke Noda, Nobuyoshi Kitaichi, Ken-Ichiro Seino, Susumu Ishida
Current eye research, 46, 12, 1908, 1916, 2021年12月, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: To investigate the immunotherapeutic effects of macrophage-like induced pluripotent stem (iPS) cell-derived suppressor cells (SCs) in ocular immune response and experimental autoimmune uveoretinitis (EAU). METHODS: The genes of Oct3/4, Sox2, Klf4, and c-Myc were transferred to B cells enriched from the spleen cells of C57BL/6 mice by using retrovirus vectors. Transferred B cells were cultured for 17 days to obtain colonies of iPS cells. Through additional steps, iPS-SCs were induced. An antigen-specific T cell proliferation assay was performed with CD4+ T cells collected from draining lymph nodes of the mice immunized with human interphotoreceptor retinoid-binding protein (hIRBP) peptide and co-cultured with iPS-SCs. Cytokine concentrations in the culture supernatant were examined. Mice were immunized with hIRBP peptide to induce EAU. The iPS-SCs were administered into the mice one day before the induction of EAU. RESULTS: The iPS-SCs decreased hIRBP-specific T cell proliferation depending on the number of cells. Productions of tumor necrosis factor-α and interferon-γ were significantly decreased; however, transforming growth factor-β1, nitric oxide, interleukin (IL)-13, IL-17A, and IL-17 F levels were elevated in the supernatant when the collected T cells were co-cultured with iPS-SCs. The iPS-SCs had immunosuppressant effects even without cell-to-cell contact, and their effects were non-specific to the antigen preloaded on iPS-SCs. EAU was significantly milder in the mice administered iPS-SCs prior to immunization. CONCLUSIONS: Macrophage-like iPS-SCs reduced Th1 immune response to a retinal antigen and Th1-mediated EAU in mice. These results showed the possibility of the application of iPS technology to the treatment of noninfectious ocular inflammation, endogenous uveitis, in the future. - 細胞・臓器の移植に伴う免疫反応とその制御-最新の研究- MHC型一致他家iPS細胞由来組織移植に有効な免疫抑制剤併用プロトコールの構築
鎌谷 智紀, 大塚 亮, 村田 智己, 和田 はるか, 高橋 武司, 森 淳祐, 村田 聡一郎, 谷口 英樹, 清野 研一郎
Organ Biology, 28, 3, 75, 75, (一社)日本臓器保存生物医学会, 2021年10月
日本語 - 死にゆくがん細胞ががん細胞ワクチン効果を発揮する
和田 はるか, 梶原 ナビール, 清野 研一郎
日本癌学会総会記事, 80回, [P12, 4], (一社)日本癌学会, 2021年09月
英語 - An optimized protocol for patient-derived xenograft in humanized mice to evaluate the role of IL-34 in immunotherapeutic resistance.
Nanumi Han, Hye Yoon Jang, Naoki Hama, Takuto Kobayashi, Ryo Otsuka, Haruka Wada, Ken-Ichiro Seino
STAR protocols, 2, 2, 100460, 100460, 2021年06月18日, ［国際誌］
英語, 研究論文（学術雑誌）, Previously, we identified a therapy-resistant role of IL-34 in an immune checkpoint blockade in murine models. To investigate whether a similar mechanism is applicable in human tumors as well, we used this protocol for the selection of IL-34-neutralizing antibody and transplanting human tumor tissue expressing both IL-34 and PD-L1 as a patient-derived xenograft in immunologically humanized mice. This model helps to determine the effect of IL-34 neutralization along with the immune checkpoint blockade in human tumors. For complete details on the use and execution of this protocol, please refer to Hama et al. (2020). - Author Correction: Efficient generation of thymic epithelium from induced pluripotent stem cells that prolongs allograft survival.
Ryo Otsuka, Haruka Wada, Hyuma Tsuji, Airi Sasaki, Tomoki Murata, Mizuho Itoh, Muhammad Baghdadi, Ken-Ichiro Seino
Scientific reports, 11, 1, 12857, 12857, 2021年06月14日, ［国際誌］
英語 - IL-34, the rationale for its expression in physiological and pathological conditions.
Ryo Otsuka, Haruka Wada, Ken-Ichiro Seino
Seminars in immunology, 54, 101517, 101517, 2021年04月, ［国際誌］
英語, 研究論文（学術雑誌）, IL-34 is a cytokine that shares one of its receptors with CSF-1. It has long been thought that CSF-1 receptor (CSF-1R) receives signals only from CSF-1, but the identification of IL-34 reversed this stereotype. Regardless of low structural homology, IL-34 and CSF-1 emanate similar downstream signaling through binding to CSF-1R and provoke similar but different physiological events afterward. In addition to CSF-1R, protein-tyrosine phosphatase (PTP)-ζ and Syndecan-1 were also identified as IL-34 receptors and shown to be at play. Although IL-34 expression is limited to particular tissues in physiological conditions, previous studies have revealed that it is upregulated in several diseases. In cancer, IL-34 is produced by several types of tumor cells and contributes to therapy resistance and disease progression. A recent study has demonstrated that tumor cell-derived IL-34 abrogates immunotherapy efficacy through myeloid cell remodeling. On the other hand, IL-34 expression is downregulated in some brain and dermal disorders. Despite accumulating insights, our understanding of IL-34 may not be even close to its nature. This review aims to comprehensively describe the physiological and pathological roles of IL-34 based on its similarity and differences to CSF-1 and discuss the rationale for its disease-dependent expression pattern. - Establishment of Human Leukocyte Antigen-Mismatched Immune Responses after Transplantation of Human Liver Bud in Humanized Mouse Models.
Akihiro Mori, Soichiro Murata, Nao Tashiro, Tomomi Tadokoro, Satoshi Okamoto, Ryo Otsuka, Haruka Wada, Tomoki Murata, Takeshi Takahashi, Ken-Ichiro Seino, Hideki Taniguchi
Cells, 10, 2, 2021年02月23日, ［国際誌］
英語, 研究論文（学術雑誌）, Humanized mouse models have contributed significantly to human immunology research. In transplant immunity, human immune cell responses to donor grafts have not been reproduced in a humanized animal model. To elicit human T-cell immune responses, we generated immune-compromised nonobese diabetic/Shi-scid, IL-2RγKO Jic (NOG) with a homozygous expression of human leukocyte antigen (HLA) class I heavy chain (NOG-HLA-A2Tg) mice. After the transplantation of HLA-A2 human hematopoietic stem cells into NOG-HLA-A2Tg, we succeeded in achieving alloimmune responses after the HLA-mismatched human-induced pluripotent stem cell (hiPSC)-derived liver-like tissue transplantation. This immune response was inhibited by administering tacrolimus. In this model, we reproduced allograft rejection after the human iPSC-derived liver-like tissue transplantation. Human tissue transplantation on the humanized mouse liver surface is a good model that can predict T-cell-mediated cellular rejection that may occur when organ transplantation is performed. - Bromodomain-containing protein 4 regulates interleukin-34 expression in mouse ovarian cancer cells
Nanumi Han, Delnur Anwar, Naoki Hama, Takuto Kobayashi, Hidefumi Suzuki, Hidehisa Takahashi, Haruka Wada, Ryo Otsuka, Muhammad Baghdadi, Ken-ichiro Seino
Inflammation and Regeneration, 40, 1, Springer Science and Business Media LLC, 2020年12月
研究論文（学術雑誌）,Abstract Background
Interleukin (IL)-34 acts as an alternative ligand for the colony-stimulating factor-1 receptor and controls the biology of myeloid cells, including survival, proliferation, and differentiation. IL-34 has been reported to be expressed in cancer cells and to promote tumor progression and metastasis of certain cancers via the promotion of angiogenesis and immunosuppressive macrophage differentiation. We have shown in our previous reports that targeting IL-34 in chemo-resistant tumors in vitro resulted in a remarkable inhibition of tumor growth. Also, we reported poor prognosis in patients with IL-34-expressing tumor. Therefore, blocking of IL-34 is considered as a promising therapeutic strategy to suppress tumor progression. However, the molecular mechanisms that control IL-34 production are still largely unknown.Methods
IL-34 producing ovarian cancer cell line HM-1 was treated by bromodomain and extra terminal inhibitor JQ1. The mRNA and protein expression of IL-34 was evaluated after JQ1 treatment. Chromatin immunoprecipitation was performed to confirm the involvement of bromodomain-containing protein 4 (Brd4) in the regulation of theIl34 gene. Anti-tumor effect of JQ1 was evaluated in mouse tumor model.Results
We identified Brd4 as one of the critical molecules that regulateIl34 expression in cancer cells. Consistent with this, we found that JQ1 is capable of efficiently suppressing the recruitment of Brd4 to the promotor region ofIl34 gene. Additionally, JQ1 treatment of mice bearing IL-34-producing tumor inhibited the tumor growth along with decreasingIl34 expression in the tumor.Conclusion
The results unveiled for the first time the responsible molecule Brd4 that regulatesIl34 expression in cancer cells and suggested its possibility as a treatment target. - A Clinical Trial With Adoptive Transfer of Ex Vivo-induced, Donor-specific Immune-regulatory Cells in Kidney Transplantation-A Second Report.
Ichiro Koyama, Hisashi Bashuda, Koichiro Uchida, Ken-Ichiro Seino, Sonoko Habu, Ichiro Nakajima, Shohei Fuchinoue, Ko Okumura, Satoshi Teraoka
Transplantation, 104, 11, 2415, 2423, 2020年11月, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Although the outcome of kidney transplantation (KTx) has improved, various adverse effects of immunosuppressants and chronic rejection aggravate the long-term prognosis of patients. Therefore, the induction of immune tolerance may be an effective therapeutic strategy. METHODS: A clinical trial aiming at immune tolerance induction was conducted in kidney transplant recipients from HLA mismatched living donors by infusing autologous donor-specific regulatory T cells (Treg). To obtain Treg, recipient's peripheral blood mononuclear cells were cocultured with irradiated donor cells in the presence of anti-CD80/CD86 monoclonal antibody for 2 weeks. For preconditioning, splenectomy + cyclophosphamide (CP) was employed in the first series (group A; n = 9). In group B, splenectomy was substituted by preadministration of rituximab (group B; n = 3). In the latest cases, rituximab + rabbit antithymocyte globulin was administered instead of cyclophosphamide (group C; n = 4). Twelve days after KTx, the cultured cells were intravenously infused, and immunosuppressants were gradually tapered thereafter. RESULTS: Although mixed lymphocyte reaction was remarkably suppressed in a donor-specific fashion, 6 out of 9 patients from group A, 1 out of 3 from group B, and 1 out of 4 from group C developed acute rejection within 1 year after KTx. Complete cessation of immunosuppression was not achieved, and a small dose of immunosuppressants was continued. CONCLUSIONS: The adoptive transfer of autologous ex vivo-expanded Treg is 1 of the options to possibly induce alloimmune hyporesponsiveness. However, in the present study, further regimen optimization is still required and should be the focus of future investigations. - Interleukin-34 contributes to poor prognosis in triple-negative breast cancer.
Nabeel Kajihara, Fumihito Kitagawa, Takuto Kobayashi, Haruka Wada, Ryo Otsuka, Ken-Ichiro Seino
Breast cancer (Tokyo, Japan), 27, 6, 1198, 1204, 2020年11月, ［国内誌］
英語, 研究論文（学術雑誌）, Triple-negative breast cancer (TNBC) is a subtype characterized by the absence of therapeutic targets. It shows rapid progression, higher relapse, and poor prognosis, so the establishment of an effective therapeutic target is required. We focused on interleukin-34 (IL-34) that is a novel cytokine relating to inflammation and tumorigenesis. It has been reported that IL-34 correlates with poor prognosis of various cancers. In this study, we evaluated the relationship of IL-34 and prognosis in TNBC using human clinical information and mice model. We found that IL-34 was highly expressed in TNBC, and the survival rate in TNBC was significantly lower in patients with high IL-34 expression. Furthermore, multivariate analysis revealed that IL-34 independently affects prognosis. In murine TNBC model, IL-34 deficiency in tumor cells decreased in vivo tumor growth and increased inflammatory cytokine production from macrophages. These results suggest that tumor-derived IL-34 creates a favorable environment for TNBC cells. Thus, we showed a novel pathological role of IL-34 in TNBC and the potential of IL-34 as a therapeutic target for it. - 腫瘍開始細胞は炎症環境を形成し免疫細胞を老化させて抗腫瘍応答の低下を導くことで免疫健常個体における腫瘍発生を許容させる
和田 はるか, 近藤 亨, 清野 研一郎
日本癌学会総会記事, 79回, OJ12, 8, (一社)日本癌学会, 2020年10月
英語 - Interleukin-34 Limits the Therapeutic Effects of Immune Checkpoint Blockade
Naoki Hama, Takuto Kobayashi, Nanumi Han, Fumihito Kitagawa, Nabeel Kajihara, Ryo Otsuka, Haruka Wada, Hee-kyung Lee, Hwanseok Rhee, Yoshinori Hasegawa, Hideo Yagita, Muhammad Baghdadi, Ken-ichiro Seino
iScience, 23, 10, 101584, 101584, Elsevier BV, 2020年10月
研究論文（学術雑誌） - 腫瘍由来Interleukin-34を標的とした新規がん治療法の確立
羽馬 直希, 小林 拓斗, 韓 ナヌミ, 北川 郁人, 梶原 ナビール, 大塚 亮, 和田 はるか, Lee Hee-kyung, Rhee Hwanseok, 長谷川 嘉則, 八木田 秀雄, Baghdadi Muhammad, 清野 研一郎
日本がん免疫学会総会プログラム・抄録集, 24回, 102, 102, 日本がん免疫学会, 2020年09月
日本語 - IL-34が大腸がん患者の予後に与える影響の解析
小林 拓斗, バグダーディ・ムハンマド, 韓 ナヌミ, 村田 智己, 大塚 亮, 和田 はるか, 宮城 洋平, 醍醐 弥太郎, 清野 研一郎
日本がん免疫学会総会プログラム・抄録集, 24回, 104, 104, 日本がん免疫学会, 2020年09月
日本語 - Establishment of an experimental model for MHC homo-to-hetero transplantation.
Tomoki Murata, Haruka Wada, Ryo Otsuka, Airi Sasaki, Hyuma Tsuji, Mizuho Itoh, Nanami Eguchi, Tatsuo Kawai, Ken-Ichiro Seino
Scientific reports, 10, 1, 13560, 13560, 2020年08月11日, ［国際誌］
英語, 研究論文（学術雑誌）, Preventing rejection is a major challenge in transplantation medicine, even when using pluripotent stem cell-derived grafts. In iPS cell (iPSC)-based transplantation, to reduce the risk of rejection, it is thought to be optimal that preparing the cells from donors whose human leukocyte antigen-haplotype are homozygous. Generally, this approach is referred to as major histocompatibility complex (MHC) homo-to-hetero transplantation, which is MHC-matched but minor antigen-mismatched. To investigate the immune response in the MHC homo-to-hetero transplantation, we established a murine experimental system in which MHC-matched but minor antigen-mismatched tissue (skin) grafts were transplanted into MHC-heterozygous recipients. Unexpectedly, only minor antigen-mismatched grafts were rejected at the same time points as rejection of fully allogeneic grafts. A vigorous anti-donor type T cell response was detected in vitro and conventional immunosuppressants targeting T cell activation had limited effects on controlling rejection. However, anti-donor antibodies were not detected only in the minor antigen-mismatched transplantation. This murine transplantation model can be used to further analyze immunological subjects for MHC homo-to-hetero iPSC-based transplantation. - Induction of macrophage-like immunosuppressive cells from common marmoset ES cells by stepwise differentiation with DZNep.
Hyuma Tsuji, Ryo Otsuka, Haruka Wada, Tomoki Murata, Airi Sasaki, Mizuho Itoh, Muhammad Baghdadi, Erika Sasaki, Ken-Ichiro Seino
Scientific reports, 10, 1, 12625, 12625, 2020年07月28日, ［国際誌］
英語, 研究論文（学術雑誌）, Recent progress in regenerative medicine has enabled the utilization of pluripotent stem cells (PSCs) as the resource of therapeutic cells/tissue. However, immune suppression is still needed when the donor-recipient combination is allogeneic. We have reported previously that mouse PSCs-derived immunosuppressive cells contribute to prolonged survival of grafts derived from the same mouse PSCs in allogeneic recipients. For its clinical application, a preclinical study using non-human primates such as common marmoset must be performed. In this study, we established the induction protocol of immunosuppressive cells from common marmoset ES cells. Although similar immunosuppressive macrophages could not be induced by same protocol as that for mouse PSCs, we employed an inhibitor for histone methyltransferase, DZNep, and succeeded to induce them. The DZNep-treated macrophage-like cells expressed several immunosuppressive molecules and significantly inhibited allogeneic mixed lymphocyte reaction. The immunosuppressive cells from non-human primate ESCs will help to establish an immunoregulating strategy in regenerative medicine using PSCs. - Steps towards COVID-19 suppression
Hideyuki Okano, Ken-Ichiro Seino
Inflammation and Regeneration, 40, 1, BioMed Central, 2020年06月22日
英語, 研究論文（学術雑誌） - 【マクロファージの功罪-疾患病態誘導と制御におけるマクロファージの役割】がん・腫瘍 IL-34とマクロファージ
小林 拓斗, 大塚 亮, 清野 研一郎
医学のあゆみ, 273, 10, 993, 998, 医歯薬出版(株), 2020年06月
日本語 - Interleukin-34 expression in ovarian cancer: a possible correlation with disease progression.
Hiraku Endo, Naoki Hama, Muhammad Baghdadi, Kozo Ishikawa, Ryo Otsuka, Haruka Wada, Hiroshi Asano, Daisuke Endo, Yosuke Konno, Tatsuya Kato, Hidemichi Watari, Akiko Tozawa, Nao Suzuki, Tomoyuki Yokose, Atsushi Takano, Hisamori Kato, Yohei Miyagi, Yataro Daigo, Ken-Ichiro Seino
International immunology, 32, 3, 175, 186, 2020年03月07日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Ovarian cancer is the second-most lethal gynecological malignancy and the seventh-commonest cause of cancer-related death in women around the world. Most of the ovarian cancer patients are diagnosed at advanced stages and suffer from recurrence after primary cytoreductive surgery and standard first-line chemotherapy. Thus, the successful management of ovarian cancer patients requires the identification of factors that contribute to progression and relapse. Interleukin-34 (IL-34) is a novel cytokine that acts as a tissue-specific ligand of colony-stimulating factor-1 receptor (CSF-1R). In cancer, IL-34 exerts pro-tumorigenic functions that promote tumor growth, metastasis, angiogenesis, immune suppression and therapeutic resistance. In this study, we evaluate the impact of IL-34 on progression and survival of ovarian cancer patients. First, IL-34 was found to be expressed in several human ovarian cancer cell lines and cancer tissues from patients. The expression of IL-34 was enhanced by cytotoxic chemotherapy in ovarian cancer cell lines and cancer tissues from chemotherapy-treated ovarian cancer patients. Importantly, high IL-34 expression correlated with worse progression-free survival (PFS) and overall survival in different cohorts. The assessment of PFS based on a combination between IL34 expression and other related genes such as CSF1R and CD163 helped further to reach more statistical significance compared with IL34 alone. Furthermore, in the murine ovarian cancer cell HM-1 in vivo model, it was suggested that IL-34-derived tumor cells was correlated with tumor progression and survival by modulating the immune environment. Collectively, these findings indicate a possible correlation between IL-34 expression and disease progression in ovarian cancer patients and the mouse model. - Efficient generation of thymic epithelium from induced pluripotent stem cells that prolongs allograft survival.
Ryo Otsuka, Haruka Wada, Hyuma Tsuji, Airi Sasaki, Tomoki Murata, Mizuho Itoh, Muhammad Baghdadi, Ken-Ichiro Seino
Scientific reports, 10, 1, 224, 224, 2020年01月14日, ［国際誌］
英語, 研究論文（学術雑誌）, The thymus plays a significant role in establishing immunological self-tolerance. Previous studies have revealed that host immune reaction to allogeneic transplants could be regulated by thymus transplantation. However, physiological thymus involution hinders the clinical application of these insights. Here, we report an efficient generation of thymic epithelial-like tissue derived from induced pluripotent stem cells (iPSCs) and its potential to regulate immune reaction in allogeneic transplantation. We established an iPSC line which constitutively expresses mouse Foxn1 gene and examined the effect of its expression during in vitro differentiation of thymic epithelial cells (TECs). We found that Foxn1 expression enhances the differentiation induction of cells expressing TEC-related cell surface molecules along with upregulation of endogenous Foxn1. iPSC-derived TECs (iPSC-TECs) generated T cells in nude recipient mice after renal subcapsular transplantation. Moreover, iPSC-TEC transplantation to immuno-competent recipients significantly prolonged the survival of allogeneic skin. Our study provides a novel concept for allogeneic transplantation in the setting of regenerative medicine. - Transcriptomic Features of T Cell-Barren Tumors Are Conserved Across Diverse Tumor Types.
Eric D Routh, Ashok K Pullikuth, Guangxu Jin, Julia Chifman, Jeff W Chou, Ralph B D'Agostino Jr, Ken-Ichiro Seino, Haruka Wada, Cristin G Print, Wei Zhang, Yong Lu, Lance D Miller
Frontiers in immunology, 11, 57, 57, 2020年, ［国際誌］
英語, 研究論文（学術雑誌）, Background: Understanding how tumors subvert immune destruction is essential to the development of cancer immunotherapies. New evidence suggests that tumors limit anti-tumor immunity by exploiting transcriptional programs that regulate intratumoral trafficking and accumulation of effector cells. Here, we investigated the gene expression profiles that distinguish immunologically "cold" and "hot" tumors across diverse tumor types. Methods: RNAseq profiles of tumors (n = 8,920) representing 23 solid tumor types were analyzed using immune gene signatures that quantify CD8+ T cell abundance. Genes and pathways associated with a low CD8+ T cell infiltration profile (CD8-Low) were identified by correlation, differential expression, and statistical ranking methods. Gene subsets were evaluated in immunotherapy treatment cohorts and functionally characterized in cell lines and mouse tumor models. Results: Among different cancer types, we observed highly significant overlap of genes enriched in CD8-Low tumors, which included known immunomodulatory genes (e.g., BMP7, CMTM4, KDM5B, RCOR2) and exhibited significant associations with Wnt signaling, neurogenesis, cell-cell junctions, lipid biosynthesis, epidermal development, and cancer-testis antigens. Analysis of mutually exclusive gene clusters demonstrated that different transcriptional programs may converge on the T cell-cold phenotype as well as predict for response and survival of patients to Nivo treatment. Furthermore, we confirmed that a top-ranking candidate belonging to the TGF-β superfamily, BMP7, negatively regulates CD8+ T cell abundance in immunocompetent murine tumor models, with and without anti-PD-L1 treatment. Conclusions: This study presents the first evidence that solid tumors of diverse anatomical origin acquire conserved transcriptional alterations that may be operative in the T cell-cold state. Our findings demonstrate the potential clinical utility of CD8-Low tumor-associated genes for predicting patient immunotherapy outcomes and point to novel mechanisms with potential for broad therapeutic exploitation. - Immune reaction and regulation in transplantation based on pluripotent stem cell technology.
Ryo Otsuka, Haruka Wada, Tomoki Murata, Ken-Ichiro Seino
Inflammation and regeneration, 40, 12, 12, 2020年, ［国際誌］
英語, 研究論文（学術雑誌）, The development of pluripotent stem cell (PSC)-based technologies provides us a new therapeutic approach that generates grafts for transplantation. In order to minimize the risk of immune reaction, the banking of induced pluripotent stem cells (iPSCs) from donors with homozygous human leukocyte antigen (HLA) haplotype is planned in Japan. Even though pre-stocked and safety validated HLA-homozygous iPSCs are selected, immunological rejection may potentially occur because the causes of rejection are not always due to HLA mismatches. A couple of studies concerning such immunological issues have reported that genetic ablation of HLA molecules from PSC combined with gene transduction of several immunoregulatory molecules may be effective in avoiding immunological rejection. Also, our research group has recently proposed a concept that attempts to regulate recipient immune system by PSC-derived immunoregulatory cells, which results in prolonged survival of the same PSC-derived allografts. PSC-based technologies enable us to choose a new therapeutic option; however, considering its safety from an immunological point of view should be of great importance for safe clinical translation of this technology. - Macrophage activation syndrome and COVID-19.
Ryo Otsuka, Ken-Ichiro Seino
Inflammation and regeneration, 40, 19, 19, 2020年, ［国際誌］
英語, 研究論文（学術雑誌）, An emerging, rapidly spreading coronavirus SARS-CoV-2 is causing a devastating pandemic. As we have not developed curative medicine and effective vaccine, the end of this life-threatening infectious disease is still unclear. Severe COVID-19 is often associated with hypercytokinemia, which is typically found in macrophage activation syndrome. SARS-CoV-2 infection causes this strong inflammation within the lung and propagates to respiratory and, ultimately, systemic organ malfunction. Although we have not fully understood the physiological and pathological aspects of COVID-19, current research progress indicates the effectiveness of anti-cytokine therapy. Here, we summarize macrophage activation syndrome and its possible contribution to COVID-19, and cytokine targeted attempts in severe COVID-19 cases. - Prognostic value of IL-34 in colorectal cancer patients.
Takuto Kobayashi, Muhammad Baghdadi, Nanumi Han, Tomoki Murata, Naoki Hama, Ryo Otsuka, Haruka Wada, Manabu Shiozawa, Tomoyuki Yokose, Yohei Miyagi, Atsushi Takano, Yataro Daigo, Ken-Ichiro Seino
Immunological medicine, 42, 4, 169, 175, 2019年12月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, The mortality of colorectal cancer is expected to increase in some countries including the United States, which necessitates the identification of new molecules that help in prognosis assessment and survival improvement. In this brief report, we evaluated the potential of interleukin-34 (IL-34) as a prognostic factor in colorectal cancer. IL-34 was reported for the first time in 2008 as a novel cytokine that controls the biology of the myeloid cell lineage. Accumulating evidence suggests important roles for IL-34 in modifying the tumor microenvironment and enhancing therapeutic resistance of cancer. In this study, we found that IL-34 expression was detectable in various colorectal cancer cell lines in addition to primary cancer tissues from a cohort of Japanese colorectal cancer patients, ranging from high to absent. A Kaplan-Meier analysis showed that high expression of IL-34 correlated with poor survival of colorectal cancer patients. Importantly, in both univariate and multivariate analysis, high IL-34 expression correlated with unfavorable prognosis. A similar relationship between IL-34 expression and the poorer prognosis was also observed in a cohort of colorectal cancer patients registered at The Cancer Genome Atlas. Together, these findings indicate a potential role for IL-34 as a prognostic factor in colorectal cancer. - Flow cytometric identification and cell-line establishment of macrophages in naked mole-rats.
Wada H, Shibata Y, Abe Y, Otsuka R, Eguchi N, Kawamura Y, Oka K, Baghdadi M, Atsumi T, Miura K, Seino KI
Scientific reports, 9, 1, 17981, 17981, 2019年11月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Naked mole rats (NMRs) have extraordinarily long lifespans and anti-tumorigenic capability. Recent studies of humans and mice have shown that many age-related diseases, including cancer, are strongly correlated with immunity, and macrophages play particularly important roles in immune regulation. Therefore, NMR macrophages may contribute to their unique phenotypes. However, studies of the roles of macrophages are limited by material restrictions and the lack of an established experimental strategy. In this study, we developed a flow cytometric strategy to identify NMR macrophages. The NMR macrophages were extractable using an off-the-shelf anti-CD11b antibody, M1/70, and forward/side scatter data obtained by flow cytometry. NMR macrophages proliferated in response to human/mouse recombinant M-CSF and engulfed Escherichia coli particles. Interestingly, the majority of NMR macrophages exhibited co-staining with an anti-NK1.1 antibody, PK136. NK1.1 antigen crosslinking with PK136 results in mouse NK cell stimulation; similarly, NMR macrophages proliferated in response to NK1.1 antibody treatment. Furthermore, we successfully established an NMR macrophage cell line, NPM1, by transduction of Simian virus 40 early region that proliferated indefinitely without cytokines and retained its phagocytotic capacity. The NPM1 would contribute to further studies on the immunity of NMRs. - がん幹細胞はそれ自身が原炎症性細胞であり微小環境に免疫老化及び免疫抑制をもたらすことで健常動物における造腫瘍能を担保する(Tumor-initiating cell induce immuno-hyporesponsiveness following cellular senescence to Mφs guarantee its tumorigenesis)
和田 はるか, バグダーディー・ムハンマド, 近藤 亨, 清野 研一郎
日本癌学会総会記事, 78回, J, 1042, (一社)日本癌学会, 2019年09月
英語 - ATLLにおけるM-CSFR発現とM-CSFR阻害剤の有効性(Potential anti-lymphoma effect of M-CSFR inhibitor in adult T-cell leukemia/lymphoma)
菰原 義弘, Muhammad Baghdadi, 清野 研一郎, 奥野 豊, 野坂 生郷, 松岡 雅雄
日本癌学会総会記事, 78回, P, 1014, 日本癌学会, 2019年09月
英語 - がん幹細胞はそれ自身が原炎症性細胞であり微小環境に免疫老化及び免疫抑制をもたらすことで健常動物における造腫瘍能を担保する
和田 はるか, 村田 智己, 大塚 亮, 森口 徹夫, バグダーディー・ムハンマド, 近藤 亨, 清野 研一郎
日本がん免疫学会総会プログラム・抄録集, 23回, 131, 131, 日本がん免疫学会, 2019年07月
日本語 - IL-34は免疫チェックポイント阻害剤の治療効果を抑制する(IL-34 limits the therapeutic effects of immune checkpoints blockade)
バグダーディー・ムハンマド, 小林 拓斗, 羽馬 直希, 韓 ナヌミ, 和田 はるか, 八木田 秀雄, 清野 研一郎
日本がん免疫学会総会プログラム・抄録集, 23回, 132, 132, 日本がん免疫学会, 2019年07月
英語 - 人工多能性幹細胞由来マクロファージ様免疫抑制細胞を用いたぶどう膜炎モデルの軽症化
長谷 敬太郎, 南場 研一, 北市 伸義, 岩田 大樹, 辻 飛雄馬, 和田 はるか, 清野 研一郎, 石田 晋
日本眼科学会雑誌, 123, 臨増, 226, 226, (公財)日本眼科学会, 2019年03月
日本語 - A role for IL-34 in osteolytic disease of multiple myeloma.
Baghdadi M, Ishikawa K, Nakanishi S, Murata T, Umeyama Y, Kobayashi T, Kameda Y, Endo H, Wada H, Bogen B, Yamamoto S, Yamaguchi K, Kasahara I, Iwasaki H, Takahata M, Ibata M, Takahashi S, Goto H, Teshima T, Seino KI
Blood advances, 3, 4, 541, 551, 2019年02月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Multiple myeloma (MM) is a hematological malignancy that grows in multiple sites of the axial skeleton and causes debilitating osteolytic disease. Interleukin-34 (IL-34) is a newly discovered cytokine that acts as a ligand of colony-stimulating factor-1 (CSF-1) receptor and can replace CSF-1 for osteoclast differentiation. In this study, we identify IL-34 as an osteoclastogenic cytokine that accelerates osteolytic disease in MM. IL-34 was found to be expressed in the murine MM cell line MOPC315.BM, and the expression of IL-34 was enhanced by stimulation with proinflammatory cytokines or by bone marrow (BM) stromal cells. MM-cell-derived IL-34 promoted osteoclast formation from mouse BM cells in vitro. Targeting Il34 by specific small interfering RNA impaired osteoclast formation in vitro and attenuated osteolytic disease in vivo. In BM aspirates from MM patients, the expression levels of IL-34 in CD138+ populations vary among patients from high to weak to absent. MM cell-derived IL-34 promoted osteoclast formation from human CD14+ monocytes, which was reduced by a neutralizing antibody against IL-34. Taken together, this study describes for the first time the expression of IL-34 in MM cells, indicating that it may enhance osteolysis and suggesting IL-34 as a potential therapeutic target to control pathological osteoclastogenesis in MM patients. - High co-expression of IL-34 and M-CSF correlates with tumor progression and poor survival in lung cancers
Muhammad Baghdadi, Hiraku Endo, Atsushi Takano, Kozo Ishikawa, Yosuke Kameda, Haruka Wada, Yohei Miyagi, Tomoyuki Yokose, Hiroyuki Ito, Haruhiko Nakayama, Yataro Daigo, Nao Suzuki, Ken-Ichiro Seino
Scientific Reports, 8, 1, Nature Publishing Group, 2018年12月01日, ［査読有り］
英語, 研究論文（学術雑誌） - iPS細胞由来組織移植に想定される拒絶反応の精査と制御法の検討
村田 智己, 和田 はるか, 大塚 亮, 辻 飛雄馬, 佐々木 愛里, 柴田 悠平, 安宅 司, 小林 拓斗, ムハンマド・バグダーディー, 清野 研一郎
移植, 53, 総会臨時, 485, 485, (一社)日本移植学会, 2018年09月
日本語 - 免疫健常個体において造腫瘍能を発揮する腫瘍開始細胞の免疫学的因子の同定(Tumor initiating cell in immunocompetent animal defined by immunological features)
和田 はるか, Baghdadi Muhammad, 森口 徹生, 近藤 亨, 清野 研一郎
日本癌学会総会記事, 77回, 2327, 2327, (一社)日本癌学会, 2018年09月
英語 - Interleukin-34, a comprehensive review.
Baghdadi M, Umeyama Y, Hama N, Kobayashi T, Han N, Wada H, Seino KI
Journal of leukocyte biology, 104, 5, 931, 951, 2018年08月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, IL-34 is a novel cytokine that was identified in 2008 in a comprehensive proteomic analysis as a tissue-specific ligand of CSF-1 receptor (CSF-1R). IL-34 exists in all vertebrates including fish, amphibians, birds, and mammals, showing high conservation among species. Structurally, IL-34 belongs to the short-chain helical hematopoietic cytokine family but shows no apparent consensus structural domains, motifs, or sequence homology with other cytokines. IL-34 is synthesized as a secreted homodimeric glycoprotein that binds to the extracellular domains of CSF-1R and receptor-type protein-tyrosine phosphatase-zeta (PTP-ζ) in addition to the chondroitin sulfate chains of syndecan-1. These interactions result in activating several signaling pathways that regulate major cellular functions, including proliferation, differentiation, survival, metabolism, and cytokine/chemokine expression in addition to cellular adhesion and migration. In the steady state, IL-34 contributes to the development and maintenance of specific myeloid cell subsets in a tissue-specific manner: Langerhans cells in the skin and microglia in the brain. In pathological conditions, changes in IL-34 expression-increased or decreased-are involved in disease pathogenesis and correlate with progression, severity, and chronicity. One decade after its discovery, IL-34 has been introduced as a newcomer to the big family of interleukins with specific physiological functions, critical pathological roles, and promising clinical applications in disease diagnosis and treatment. In this review, we celebrate the 10th anniversary of IL-34 discovery, introducing its biological characteristics, and discussing the importance of IL-34 signaling network in health and disease. - 肺癌におけるIL-34と治療耐性、疾患進行、予後不良との関連(IL-34 correlates with therapeutic resistance, disease progression, and poor prognosis in lung cancers)
バグダーディー・ムハンマド, 和田 はるか, 清野 研一郎
日本がん免疫学会総会プログラム・抄録集, 22回, 111, 111, 日本がん免疫学会, 2018年07月
英語 - がん細胞ワクチンの効果発揮には死細胞でなく「死にゆく」細胞が重要である
和田 はるか, 安宅 司, 田中 睦乃, バグダーディー・ムハンマド, 清野 研一郎
日本がん免疫学会総会プログラム・抄録集, 22回, 151, 151, 日本がん免疫学会, 2018年07月
日本語 - Enhanced expression of IL-34 in an inflammatory cyst of the submandibular gland: a case report.
Baghdadi M, Ishikawa K, Endo H, Umeyama Y, Ataka T, Wada H, Oyamada Y, Hyakushima N, Seino KI
Inflammation and regeneration, 38, 12, 12, 12, 2018年07月, ［査読有り］, ［国際誌］
英語, Background: Cysts of the salivary glands are common lesions that occur in the context of various etiologies. Although the diagnostic importance of cysts in salivary gland diseases has been well studied, molecular mechanisms that control the related pathological process remain largely unknown. IL-34 is a novel cytokine that was discovered recently as a tissue-specific ligand of colony stimulating factor-1 receptor. Since its discovery, accumulating evidence has revealed emerging roles of IL-34 in various pathological conditions and has been suggested to correlate remarkably with inflammation. In this study, we report a medical case of an inflammatory cyst within the submandibular gland, through which evaluating the possible involvement of IL-34 in salivary gland disorders. Case presentation: A 37-year-old male patient suffered from a sudden swelling in the right submandibular region, started initially small and had gradually increased in size to reach 3-4 cm in 1 week, accompanied by pain and local fever. Ultrasonography and MRI imaging revealed the existence of a well-defined cystic lesion with sharp borders measuring 39.8 mm × 19.7 mm within the right submandibular gland. The cyst was removed surgically, and the diagnostic decision was determined based on histopathological observations as an inflammatory cyst in the submandibular gland. Sections were generated from different regions of the surgically resected inflammatory cyst and used to examine IL-34 expression by immunohistochemistry compared to normal salivary gland tissues. Immunohistochemical staining showed enhanced expression of IL-34 in the ductal epithelial cells and endothelial cells of blood vessels, with a tendency to be accompanied with high infiltration of immune cells, which suggests a possible involvement of IL-34 in the pathogenesis of salivary gland inflammation. Conclusions: In this report, we introduce interesting findings of enhanced IL-34 expression in a case of an inflamed submandibular gland. Our findings emphasize the pathological roles of IL-34 as an inflammation amplifier and angiogenic enhancer in inflammatory conditions, such as in salivary gland disorders. - 免疫療法の新たなステージへ ～Interleukin-34標的薬の可能性～
羽馬直希, 韓ナヌミ、ムハンマド・バグダーディー, 清野研一郎
日本免疫治療学会誌, 6, 3, 6, 2018年06月, ［査読有り］, ［招待有り］
日本語 - Enhanced IL-34 expression in Nivolumab-resistant metastatic melanoma.
Han N, Baghdadi M, Ishikawa K, Endo H, Kobayashi T, Wada H, Imafuku K, Hata H, Seino KI
Inflammation and regeneration, 38, 3, 3, 3, 2018年03月, ［査読有り］, ［国際誌］
英語, BACKGROUND: Immunotherapies that target immune-checkpoint molecules such PD-1 have helped to achieve durable responses in melanoma treatment. However, 25% of melanoma patients who showed objective responses to PD-1 blockade develop resistance and suffer from disease progression and ultimately death, which necessitates the identification of related resistance mechanisms.IL-34 is a cytokine that controls the biology of myeloid cell lineage through binding to CSF-1R. IL-34 is importantly involved in the pathogenesis of various diseases. In cancer, the expression of IL-34 has been suggested to associate with tumor growth, metastasis, angiogenesis, and therapeutic resistance such as in lung cancers and malignant pleural mesotheliomas. In this study, we evaluate the possible involvement of IL-34 in immunotherapeutic resistance. CASE PRESENTATION: Melanoma resection species were obtained from a patient who developed a refractory melanoma against immunotherapy with Nivolumab, and stained with anti-IL-34, anti-melanoma antigens and anti-CD163 antibody. Staining of these markers was compared between primary or metastatic refractory melanoma tissues. Immunohistochemistry staining of melanoma tissues showed an enhanced expression of IL-34 in metastatic refractory melanoma compared to primary melanoma tissues, which correlates with increased frequencies of CD163+ macrophages. CONCLUSION: We introduce for the first time a clinical case of a patient with metastatic refractory melanoma that acquired resistance to anti-PD-1 immunotherapy, showing an enhanced expression of IL-34 in refractory melanoma tissues. - Potential anti-lymphoma effect of M-CSFR inhibitor in adult T-cell leukemia/lymphoma.
Yoshihiro Komohara, Osamu Noyori, Yoichi Saito, Hiroto Takeya, Muhammad Baghdadi, Fumihito Kitagawa, Naoki Hama, Kozo Ishikawa, Yutaka Okuno, Kisato Nosaka, Ken-Ichiro Seino, Masao Matsuoka, Shinya Suzu
Journal of clinical and experimental hematopathology : JCEH, 58, 4, 152, 160, 2018年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, The c-fms proto-oncogene is also known as macrophage colony stimulating factor receptor (M-CSFR) or colony-stimulating factor-1 receptor (CSF-1R), and is expressed on several types of malignant tumor cells and myeloid cells. In the present study, we found that overexpression of M-CSFR was present in adult T-cell leukemia/lymphoma (ATLL) cases. M-CSFR signaling was associated with lymphoma cell proliferation, and M-CSFR inhibition induced apoptosis in lymphoma cells. The ATLL cell line ATL-T expressed M-CSF/CSF-1 and interleukin (IL)-34, which are both M-CSFR ligands. M-CSF and IL-34 expression was seen in ATLL cases, and co-expression of these ligands was detected in 11 of 13 ATLL cases. M-CSFR inhibition suppressed programmed death-1 and -2 ligand in ATL-T cells and macrophages stimulated with conditioned medium from ATL-T cells. Thus, an M-CSFR inhibitor may be useful as additional therapy against ATLL due to direct and indirect mechanisms. - Interleukin 34, from pathogenesis to clinical applications
Muhammad Baghdadi, Hiraku Endo, Yoshino Tanaka, Haruka Wada, Ken-ichiro Seino
CYTOKINE, 99, 139, 147, 2017年11月, ［査読有り］
英語 - Intravenous dendritic cell administration enhances suppression of lung metastasis induced by carbon-ion irradiation
Ken Ando, Hidetoshi Fujita, Akihiro Hosoi, Liqiu Ma, Masaru Wakatsuki, Ken-ichiro Seino, Kazuhiro Kakimi, Takashi Imai, Takashi Shimokawa, Takashi Nakano
JOURNAL OF RADIATION RESEARCH, 58, 4, 446, 455, 2017年07月, ［査読有り］
英語, 研究論文（学術雑誌） - マウスiPS細胞から誘導した制御性マクロファージ様細胞によるアログラフト生着延長の検討
佐々木 元, 和田 はるか, 森田 研, 清野 研一郎, 篠原 信雄
泌尿器外科, 30, 6, 1067, 1067, 医学図書出版(株), 2017年06月
日本語 - 化学療法誘発性のIL-34はオートクラインの機序により化学療法耐性腫瘍細胞の生存を促進する(Chemotherapy-induced IL-34 promotes survival of chemoresistant cancer cells via autocrine mechanism)
Putra Wira Eka, Baghdadi Muhammad, 和田 はるか, 清野 研一郎
日本がん免疫学会総会プログラム・抄録集, 21回, 115, 115, 日本がん免疫学会, 2017年06月
英語 - 腫瘍始原細胞の免疫学的な特徴(Immunological features of tumor initiating cells)
和田 はるか, Baghdadi Muhammad, 清野 研一郎
日本がん免疫学会総会プログラム・抄録集, 21回, 121, 121, 日本がん免疫学会, 2017年06月
英語 - 多発性骨髄腫においてIL-34は破骨細胞の形成を促進し骨疾患を増悪化させる(IL-34 promotes ostelcclast formation and enhances bone disease in multiple myeloma)
Baghdadi Muhammad, 石川 浩三, 和田 はるか, 清野 研一郎
日本がん免疫学会総会プログラム・抄録集, 21回, 145, 145, 日本がん免疫学会, 2017年06月
英語 - Chemotherapy-Induced IL34 Enhances Immunosuppression by Tumor-Associated Macrophages and Mediates Survival of Chemoresistant Lung Cancer Cells
Muhammad Baghdadi, Haruka Wada, Sayaka Nakanishi, Hirotake Abe, Nanumi Han, Wira Eka Putra, Daisuke Endo, Hidemichi Watari, Noriaki Sakuragi, Yasuhiro Hida, Kichizo Kaga, Yohei Miyagi, Tomoyuki Yokose, Atsushi Takano, Yataro Daigo, Ken-ichiro Seino
CANCER RESEARCH, 76, 20, 6030, 6042, 2016年10月, ［査読有り］
英語, 研究論文（学術雑誌） - Transcriptional regulator Bhlhe40 works as a cofactor of T-bet in the regulation of IFN-γ production in iNKT cells.
Kanda M, Yamanaka H, Kojo S, Usui Y, Honda H, Sotomaru Y, Harada M, Taniguchi M, Suzuki N, Atsumi T, Wada H, Baghdadi M, Seino K
Proceedings of the National Academy of Sciences of the United States of America, 113, 24, E3394, E3402, 2016年06月, ［査読有り］
英語, 研究論文（学術雑誌） - Tumour resistance in induced pluripotent stem cells derived from naked mole-rats
Shingo Miyawaki, Yoshimi Kawamura, Yuki Oiwa, Atsushi Shimizu, Tsuyoshi Hachiya, Hidemasa Bono, Ikuko Koya, Yohei Okada, Tokuhiro Kimura, Yoshihiro Tsuchiya, Sadafumi Suzuki, Nobuyuki Onishi, Naoko Kuzumaki, Yumi Matsuzaki, Minoru Narita, Eiji Ikeda, Kazuo Okanoya, Ken-ichiro Seino, Hideyuki Saya, Hideyuki Okano, Kyoko Miura
NATURE COMMUNICATIONS, 7, 11471, 2016年05月, ［査読有り］
英語, 研究論文（学術雑誌） - 多発性骨髄腫由来IL-34による破骨細胞誘導と骨破壊性疾患に対する影響
バグダーディ・ムハンマド, 中西 沙耶香, 和田 はるか, 清野 研一郎
International Journal of Myeloma, 6, 2, 125, 125, (一社)日本骨髄腫学会, 2016年04月
日本語 - Identification of a highly immunogenic mouse breast cancer sub cell line, 4T1-S
Hirotake Abe, Haruka Wada, Muhammad Baghdadi, Sayaka Nakanishi, Yuu Usui, Takahiro Tsuchikawa, Toshiaki Shichinohe, Satoshi Hirano, Ken-ichiro Seino
HUMAN CELL, 29, 2, 58, 66, 2016年04月, ［査読有り］
英語, 研究論文（学術雑誌） - Identification of a highly immunogenic mouse breast cancer sub cell line, 4t1-s
Hirotake Abe, Haruka Wada, Muhammad Baghdadi, Sayaka Nakanishi, Yuu Usui, Takahiro Tsuchikawa, Toshiaki Shichinohe, Satoshi Hirano, Ken-Ichiro Seino
Human Cell, 29, 2, 58, 66, Springer Tokyo, 2016年, ［査読有り］
英語, 研究論文（学術雑誌） - Invariant natural killer T cell deficiency leads to the development of spontaneous liver inflammation dependent on γδT cells in mice.
Nishio K, Miyagi T, Tatsumi T, Mukai K, Yokoyama Y, Yoshioka T, Sakamori R, Hikita H, Kodama T, Shimizu S, Shigekawa M, Nawa T, Yoshihara H, Hiramatsu N, Yamanaka H, Seino K, Takehara T
Journal of gastroenterology, 50, 11, 1124, 1133, 2015年11月, ［査読有り］
英語, 研究論文（学術雑誌） - New Immunosuppressive Cell Therapy to Prolong Survival of Induced Pluripotent Stem Cell-Derived Allografts
Hajime Sasaki, Haruka Wada, Muhammad Baghdadi, Hyuma Tsuji, Ryo Otsuka, Ken Morita, Nobuo Shinohara, Ken-ichiro Seino
TRANSPLANTATION, 99, 11, 2301, 2310, 2015年11月, ［査読有り］
英語, 研究論文（学術雑誌） - Generation of T-lineage cells from iPS cells and its application
Haruka Wada, Muhammad Baghdadi, Ken-Ichiro Seino
Hematopoietic Differentiation of Human Pluripotent Stem Cells, 81, 90, Springer Netherlands, 2015年08月25日, ［査読有り］
英語, 論文集(書籍)内論文 - Myeloid molecular characteristics of human γδ T cells support their acquisition of tumor antigen-presenting capacity.
Muto M, Baghdadi M, Maekawa R, Wada H, Seino K
Cancer immunology, immunotherapy : CII, 64, 8, 941, 949, 2015年08月, ［査読有り］
英語, 研究論文（学術雑誌） - Chemotherapy-Derived Inflammatory Responses Accelerate the Formation of Immunosuppressive Myeloid Cells in the Tissue Microenvironment of Human Pancreatic Cancer
Shintaro Takeuchi, Muhammad Baghdadi, Takahiro Tsuchikawa, Haruka Wada, Toru Nakamura, Hirotake Abe, Sayaka Nakanishi, Yuu Usui, Kohtaro Higuchi, Mizuna Takahashi, Kazuho Inoko, Syoki Sato, Hironobu Takano, Toshiaki Shichinohe, Ken-ichiro Seino, Satoshi Hirano
CANCER RESEARCH, 75, 13, 2629, 2640, 2015年07月, ［査読有り］
英語, 研究論文（学術雑誌） - 多能性幹細胞を用いた再生医療における新しい免疫制御法
和田はるか, 工藤浩也, 佐々木元, Muhammad Baghdadi, 清野研一郎
日本臨床, 73, 5, 90, 95, 2015年06月, ［査読有り］, ［招待有り］
日本語 - マウスiPS細胞から誘導した制御性マクロファージ様細胞によるiPS細胞由来アログラフトの生着延長効果
佐々木 元, 和田 はるか, 森田 研, 清野 研一郎, 篠原 信雄
泌尿器外科, 28, 5, 1012, 1012, 医学図書出版(株), 2015年05月
日本語 - マウスiPS細胞から誘導した制御性マクロファージ様細胞によるアログラフト生着延長の検討
佐々木 元, 和田 はるか, 森田 研, 清野 研一郎, 篠原 信雄
日本泌尿器科学会総会, 103回, 518, 518, (一社)日本泌尿器科学会総会事務局, 2015年04月
日本語 - New immunosuppressive strategies for transplantation based on pluripotent stem cell (PSC)-derived immunoregulatory cells
Stem Cell and Translational Investigation, 2015年02月, ［査読有り］ - α-MSH stimulation contributes to TGF-β1 production via MC1R-MITF signaling pathway in melanoma cell
Hayashi Erika, Hachiya Kaori, Kojo Satoshi, Baghdadi Muhammad, Takeuchi Shintaro, Yamanaka Hiroyuki, Abe Hirotak, Wada Haruka, Seino Ken-ichiro
Inflammation and Regeneration, 35, 5, 244, 254, 日本炎症・再生医学会, 2015年
日本語, Transforming growth factor-β (TGF-β) is a multifunctional cytokine that play critical roles in melanoma progression. Although the impact of TGF-β signaling on melanoma progression has been well characterized, little is known about the molecular mechanisms that control TGF-β production in melanoma cells. In this study, we describe a novel role for Melanocortin Receptor 1 (MC1R) in the regulation of TGF-β production. MC1R is a cell surface endocytic receptor expressed in melanoma cells and serves as a receptor for α-Melanocyte Stimulating Hormone (α-MSH). The activation of MC1R with α-MSH resulted in increased levels of TGF-β, which was mediated by ERK1/2 and p38 signaling pathways. Furthermore, Microphthalmia Transcription Factor (MITF), the master regulator of melanocytes, was found to act downstream of MC1R to regulate TGF-β production. Targeting of MC1R-MITF axis was effective to decrease TGF-β production, and resulted in delayed tumor growth of B16 melanoma in vivo. Collectively, these results give new insight into the molecular mechanisms that control TGF-β production in melanoma cells. - New immune regulation strategy in the age of regenerative medicine using pluripotent stem cells
Wada Haruka, Kudo Hiroya, Sasaki Hajime, Baghdadi Muhammad, Seino Ken-ichir
Inflammation and Regeneration, 35, 5, 238, 243, 日本炎症・再生医学会, 2015年
日本語, Recent progress of manipulating pluripotent stem cells expands possibilities of regenerative medicine and opens novel transplantation medicine. However, in many cases of these medicines, the relationship between therapeutic cells and recipients would be allogeneic. In this context, we proposed new concept of immune regulation therapy in new-age medicine using pluripotent stem cells. In our concept, not only grafts but also immune regulating cells are generated from pluripotent stem cells by exertion of its pluripotency. We have recently developed immune suppressive macrophage-like cells from pluripotent stem cells. These cells suppressed allo-antigen stimulated T cell proliferation in an iNOS dependent manner. Furthermore, these immune suppressive macrophage-like cells derived from pluripotent stem cells prolonged survival of grafts derived from same pluripotent stem cells in allogeneic recipients. Thus, series of our study proved the efficacy of our new immune regulating strategy in the age of regenerative medicine which utilize pluripotent stem cells as a therapeutic cell source. - Induction of Macrophage-Like Immunosuppressive Cells from Mouse ES Cells That Contribute to Prolong Allogeneic Graft Survival
Hiroya Kudo, Haruka Wada, Hajime Sasaki, Hyuma Tsuji, Ryo Otsuka, Muhammad Baghdadi, Satoshi Kojo, Tatsuya Chikaraishi, Ken-ichiro Seino
PLOS ONE, 9, 10, e111826, 2014年10月, ［査読有り］
英語, 研究論文（学術雑誌） - 膵癌は化学療法投与環境下でMyeloid derived suppressor cellの形成を促進する(Pancreatic cancer facilitates myeloid derived suppressor cell formation under chemotherapy treated conditions)
武内 慎太郎, 土川 貴裕, 和田 はるか, 中村 透, 七戸 俊明, 清野 研一郎, 平野 聡
日本癌学会総会記事, 73回, E, 2042, (一社)日本癌学会, 2014年09月
英語 - Blocking monoclonal antibodies of TIM proteins as orchestrators of anti-tumor immune response
Muhammad Baghdadi, Shintaro Takeuchi, Haruka Wada, Ken-ichiro Seino
MABS, 6, 5, 1124, 1132, 2014年09月, ［査読有り］
英語 - マウスiPS細胞から誘導した制御性マクロファージ様細胞によるMLRアロT細胞増殖抑制の検討
佐々木 元, 和田 はるか, 清野 研一郎
日本移植学会総会プログラム抄録集, 50回, 359, 359, (一社)日本移植学会, 2014年08月
日本語 - コモンマーモセットES細胞由来免疫制御細胞による免疫寛容誘導の試み
辻 飛雄馬, 和田 はるか, 佐々木 えりか, 清野 研一郎
日本移植学会総会プログラム抄録集, 50回, 359, 359, (一社)日本移植学会, 2014年08月
日本語 - 多能性幹細胞由来胸腺組織による中枢性寛容誘導の試み
大塚 亮, 和田 はるか, 清野 研一郎
日本移植学会総会プログラム抄録集, 50回, 446, 446, (一社)日本移植学会, 2014年08月
日本語 - 小型霊長類コモンマーモセットの多能性幹細胞を用いた免疫抑制細胞の誘導
辻 飛雄馬, 和田 はるか, 清野 研一郎, 佐々木 えりか
北海道外科雑誌, 59, 1, 91, 91, 北海道外科学会, 2014年06月
日本語 - ワクチン効果の異なるマウス乳がん細胞株の比較・検討によるワクチン効果増強因子の検索
阿部 紘丈, 和田 はるか, 林 えりか, 山中 弘之, 武内 慎太郎, 平野 聡, 清野 研一郎
日本がん免疫学会総会プログラム・抄録集, 18回, 155, 155, 日本がん免疫学会, 2014年06月
日本語 - 多能性幹細胞を用いた免疫抑制療法
工藤 浩也, 和田 はるか, 佐々木 元, 辻 飛雄馬, 香城 諭, 清野 研一郎, 力石 辰也
日本泌尿器科学会総会, 102回, 429, 429, (一社)日本泌尿器科学会総会事務局, 2014年04月
日本語 - マウスiPS細胞から誘導した制御性マクロファージ様細胞によるMLRアロT細胞増殖抑制の検討
佐々木 元, 和田 はるか, 香城 論, 清野 研一郎, 野々村 克也
日本泌尿器科学会総会, 102回, 621, 621, (一社)日本泌尿器科学会総会事務局, 2014年04月
日本語 - Treg-enriched CD4+T cells attenuate collagen synthesis in keloid fibroblasts
Naoki Murao, Ken-ichiro Seino, Toshihiko Hayashi, Masaki Ikeda, Emi Funayama, Hiroshi Furukawa, Yuhei Yamamoto, Akihiko Oyama
EXPERIMENTAL DERMATOLOGY, 23, 4, 266, 271, 2014年04月, ［査読有り］
英語, 研究論文（学術雑誌） - 【再生医療の最新の進歩(前篇) 次世代再生医療に向けた基盤研究】再生医療普及のための基盤技術 再生医療における免疫制御
佐々木 元, 和田 はるか, 清野 研一郎
最新医学, 69, 3月増刊, 707, 713, (株)最新医学社, 2014年03月
日本語 - Donor specific hyporesponsiveness in kidney transplantation using adoptive transfer of ex vivo induced tolerogenic cells
Koyama Ichiro, Bashuda Hisashi, Seino Ken-Ichiro, Kai Kotaro, Sannomiya Akihito, Murakami Toru, Nakajima Ichiro, Nakajima Ichiro, Fuchinoue Shohei, Okumura Ko, Teraoka Satoshi
XENOTRANSPLANTATION, 20, 5, 375, 376, 2013年09月, ［査読有り］ - Mouse models of human INAD by Pla2g6 deficiency
Haruka Wada, Satoshi Kojo, Ken-ichiro Seino
HISTOLOGY AND HISTOPATHOLOGY, 28, 8, 965, 969, 2013年08月, ［査読有り］
英語 - 【臓器移植臨床における免疫寛容導入の試みと現状】細胞治療による免疫寛容の誘導
工藤 浩也, 和田 はるか, 清野 研一郎
今日の移植, 25, 4, 293, 300, (株)日本医学館, 2012年08月
日本語 - Role of gamma delta T cells in the regulation of HTLV-1 infection
Tomoo Sato, Masato Muto, Natsumi Araya, Satoshi Kojo, Ariyoshi Naoko, Ryuji Maekawa, Atae Utsunomiya, Ken-ichiro Seino, Yoshihisa Yamano
JOURNAL OF NEUROVIROLOGY, 18, 100, 101, 2012年05月, ［査読有り］
英語 - 次世代の移植医療に向けて 先端技術を応用した移植医療の開発 多能性幹細胞を用いた新しい免疫制御法に関する研究
工藤 浩也, 和田 はるか, 香城 諭, 力石 辰也, 清野 研一郎
移植, 46, 総会臨時, 126, 126, (一社)日本移植学会, 2011年10月
日本語 - iPSテクノロジーを導入した新しいがん免疫細胞療法の確立に向けた取り組みと現状
和田 はるか, 細井 亮宏, 垣見 和宏, 清野 研一郎
日本がん免疫学会総会プログラム・抄録集, 15回, 104, 104, 日本がん免疫学会, 2011年06月
日本語 - Side population is increased in paclitaxel-resistant ovarian cancer cell lines regardless of resistance to cisplatin
Yoichi Kobayashi, Ken-ichiro Seino, Shinji Hosonuma, Tatsuru Ohara, Hiroaki Itamochi, Seiji Isonishi, Tsunekazu Kita, Haruka Wada, Satoshi Kojo, Kazushige Kiguchi
GYNECOLOGIC ONCOLOGY, 121, 2, 390, 394, 2011年05月, ［査読有り］
英語, 研究論文（学術雑誌） - Clinical significance of side population in ovarian cancer cells
Shinji Hosonuma, Yoichi Kobayashi, Satoshi Kojo, Haruka Wada, Ken-ichiro Seino, Kazushige Kiguchi, Bunpei Ishizuka
Human Cell, 24, 1, 9, 12, 2011年03月, ［査読有り］
英語, 研究論文（学術雑誌） - Clinical significance of side population in ovarian cancer cells
Shinji Hosonuma, Yoichi Kobayashi, Satoshi Kojo, Haruka Wada, Ken-ichiro Seino, Kazushige Kiguchi, Bunpei Ishizuka
HUMAN CELL, 24, 1, 9, 12, 2011年, ［査読有り］
英語, 研究論文（学術雑誌） - Successful differentiation to T cells, but unsuccessful B-cell generation, from B-cell-derived induced pluripotent stem cells
Haruka Wada, Satoshi Kojo, Chie Kusama, Naoki Okamoto, Yorino Sato, Bunpei Ishizuka, Ken-ichiro Seino
INTERNATIONAL IMMUNOLOGY, 23, 1, 65, 74, 2011年01月, ［査読有り］
英語, 研究論文（学術雑誌） - Combining carbon ion radiotherapy and local injection of α-galactosylceramide-pulsed dendritic cells inhibits lung metastases in an in vivo murine model.
Ohkubo Y, Iwakawa M, Seino K, Nakawatari M, Wada H, Kamijuku H, Nakamura E, Nakano T, Imai T
International journal of radiation oncology, biology, physics, 78, 5, 1524, 1531, 2010年12月, ［査読有り］
英語, 研究論文（学術雑誌） - iPS細胞を用いた新しい免疫細胞再生医療の可能性(DLIモデルによる検討)
和田 はるか, 清野 研一郎
日本がん免疫学会総会プログラム・抄録集, 14回, 55, 55, 日本がん免疫学会, 2010年07月
日本語 - インフルエンザ感染におけるCTLA4-Igの効果
神宿 元, 香城 諭, 和田 はるか, 清野 研一郎
リウマチ科, 43, 3, 291, 297, (有)科学評論社, 2010年03月
日本語 - Establishment of an Improved Mouse Model for Infantile Neuroaxonal Dystrophy That Shows Early Disease Onset and Bears a Point Mutation in Pla296
Haruka Wada, Takuwa Yasuda, Ikuo Miura, Kazuhiko Watabe, Chika Sawa, Hajime Kamijuku, Satoshi Kojo, Masaru Taniguchi, Ichizo Nishino, Shigeharu Wakana, Hisahiro Yoshida, Ken-ichiro Seino
AMERICAN JOURNAL OF PATHOLOGY, 175, 6, 2257, 2263, 2009年12月, ［査読有り］
英語, 研究論文（学術雑誌） - 免疫制御分子とがん免疫療法 Zoledronateにより活性化させたγδT細胞の抗原提示能に関する検討
武藤 真人, 富山 舞, 贄田 美江, 前川 隆司, 香城 諭, 和田 はるか, 清野 研一郎
日本免疫学会総会・学術集会記録, 39, 199, 199, (NPO)日本免疫学会, 2009年11月
日本語 - Severe loss of invariant NKT cells exhibiting anti-HTLV-1 activity in patients with HTLV-1-associated disorders
Kazuko Azakami, Tomoo Sato, Natsumi Araya, Atae Utsunomiya, Ryuji Kubota, Kenshi Suzuki, Daisuke Hasegawa, Toshihiko Izumi, Hidetoshi Fujita, Satoko Aratani, Ryoji Fujii, Naoko Yagishita, Hajime Kamijuku, Takuro Kanekura, Ken-ichiro Seino, Kusuki Nishioka, Toshihiro Nakajima, Yoshihisa Yamano
BLOOD, 114, 15, 3208, 3215, 2009年10月, ［査読有り］
英語, 研究論文（学術雑誌） - The study of regulatory T cells and NKT cells in Japan: a historical perspective
Hisashi Arase, Ken-ichiro Seino
INTERNATIONAL IMMUNOLOGY, 21, 10, 1101, 1103, 2009年10月, ［査読有り］
英語 - Research highlights: Immunomodulation.
Wada H, Kojo S, Seino K
Immunotherapy, 1, 5, 737, 739, 2009年09月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌） - Cell therapy(細胞療法)の新たなアプローチ ES細胞と人工多能性幹細胞(iPS)細胞由来の機能的T細胞のin vitro作製(Generation of functional T cells from ES cells and induced pluripotent stem (iPS) cells in vitro)
和田 はるか, 清野 研一郎
日本がん免疫学会総会プログラム・抄録集, 13回, 36, 36, 日本がん免疫学会, 2009年06月
英語 - 樹状細胞 マウスモデルを用いた炭素イオン線照射・樹状細胞療法併用による肺転移抑制効果
大久保 悠, 岩川 眞由美, 神宿 元, 和田 はるか, 清野 研一郎
日本がん免疫学会総会プログラム・抄録集, 13回, 46, 46, 日本がん免疫学会, 2009年06月
日本語 - Cancellation of NKT cell immunosuppression targeting myeloid suppressor cells
Wada Haruka, Yanagisawa Kazuhiko, Seino Ken-ichiro
炎症・再生 : 日本炎症・再生医学会雑誌 = Inflammation and regeneration, 29, 2, 128, 130, 日本炎症・再生医学会, 2009年03月25日
英語, CD1d-restricted natural killer T (NKT) cells are one of immunoregulatory cells. NKT cells can be specifically activated by a synthetic glycolipid, α-galactosylceramide (α-GalCer). Using some glycolipids such as α-GalCer, it is expected to develop a new NKT cell-mediated therapeutic strategy against cancer. However, it is known that, in human cancer patients, NKT cells express a degree of hyporesponsiveness to α-GalCer. For example, we have reported that, in gastrointestinal cancer patients, NKT cell proliferation and cytokine production were impaired. We have further examined the mechanism by which hyporesponsiveness to α-GalCer can be induced using cancer-bearing mice. In the animal study, α-GalCer-induced NKT cell expansion, cytokine production, cytotoxicity, and anti-metastatic effect in vivo were all significantly impaired. In fact, α-GalCer could eliminate metastatic disease in naive animals, but failed to protect cancer-bearing mice. We found that CD11b<SUP>+</SUP> Gr-1<SUP>+</SUP> cells were particularly increased in cancer-bearing mice and were necessary and sufficient for the suppression of NKT cells to α-GalCer. We also found that the increased CD11b<SUP>+</SUP> Gr-1<SUP>+</SUP> cells suppressed NKT cell function in a nitric oxide-mediated fashion. To reduce the population of CD11b<SUP>+</SUP> Gr-1<SUP>+</SUP> cells, we administered a retinoic acid to cancer-bearing mice. This treatment significantly reduced the population of CD11b<SUP>+</SUP> Gr-1<SUP>+</SUP> cells and effectively restored α-GalCer-induced NKT cell responses. These results demonstrate a novel feature of NKT cell function in cancer, and suggest a new strategy to enhance NKT cell-mediated anti-cancer immune responses by suppressing CD11b<SUP>+</SUP> Gr-1<SUP>+</SUP> cell functions. - ENU誘発PLA2G6変異マウス ヒト乳児型軸索ジストロフィーモデルの樹立
渡部 和彦, 和田 はるか, 高澤 隆紀, 澤 智華, 秋山 けい子, 安田 琢和, 吉田 尚弘, 西野 一三, 清野 研一郎
臨床神経学, 48, 12, 1116, 1116, (一社)日本神経学会, 2008年12月, ［査読有り］
日本語 - RCAI-17, 22, 24-26, 29, 31, 34-36, 38-40, and 88, the analogs of KRN7000 with a sulfonamide linkage: Their synthesis and bioactivity for mouse natural killer T cells to produce Th2-biased cytokines
Takuya Tashiro, Naomi Hongo, Ryusuke Nakagawa, Ken-ichiro Seino, Hiroshi Watarai, Yasuyuki Ishii, Masaru Taniguchi, Kenji Mori
BIOORGANIC & MEDICINAL CHEMISTRY, 16, 19, 8896, 8906, 2008年10月, ［査読有り］
英語, 研究論文（学術雑誌） - Mechanism of NKT cell activation by intranasal coadministration of alpha-galactosylceramide, which can induce cross-protection against influenza viruses
H. Kamijuku, Y. Nagata, X. Jiang, T. Ichinohe, T. Tashiro, K. Mori, M. Taniguchi, K. Hase, H. Ohno, T. Shimaoka, S. Yonehara, T. Odagiri, M. Tashiro, T. Sata, H. Hasegawa, K-i Seino
MUCOSAL IMMUNOLOGY, 1, 3, 208, 218, 2008年05月, ［査読有り］
英語, 研究論文（学術雑誌） - Distinct regulatory functions of SLP-76 and MIST in NK cell cytotoxicity and IFN-gamma production
Shinya Hidano, Hiroki Sasanuma, Keiko Ohshima, Ken-Ichiro Seino, Lalit Kumar, Katsuhiko Hayashi, Masaki Hikida, Tomohiro Kurosaki, Masaru Taniguchi, Raif S. Geha, Daisuke Kitamura, Ryo Goitsuka
INTERNATIONAL IMMUNOLOGY, 20, 3, 345, 352, 2008年03月, ［査読有り］
英語, 研究論文（学術雑誌） - RCAI-8, 9, 18, 19, and 49-52, conformationally restricted analogues of KRN7000 with an azetidine or a pyrrolidine ring: Their synthesis and bioactivity for mouse natural killer T cells to produce cytokines
Ken-ichi Fuhshuku, Naomi Hongo, Takuya Tashiro, Yui Masuda, Ryusuke Nakagawa, Ken-ichiro Seino, Masaru Taniguchi, Kenji Mori
BIOORGANIC & MEDICINAL CHEMISTRY, 16, 2, 950, 964, 2008年01月, ［査読有り］
英語, 研究論文（学術雑誌） - Critical role for CXC chemokine ligand 16 (SR-PSOX) in Th1 response mediated by NKT cells
Takeshi Shimaoka, Ken-ichiro Seino, Noriaki Kume, Manabu Minami, Chiyoko Nishime, Makoto Suematsu, Toru Kita, Masaru Taniguchi, Kouji Matsushima, Shin Yonehara
JOURNAL OF IMMUNOLOGY, 179, 12, 8172, 8179, 2007年12月, ［査読有り］
英語, 研究論文（学術雑誌） - Construction of an open-access database that integrates cross-reference information from the transcriptome and proteome of immune cells
Atsushi Hijikata, Hiroshi Kitamura, Yayoi Kimura, Ryo Yokoyama, Yuichi Aiba, Yanyuan Bao, Shigeharu Fujita, Koji Hase, Shohei Hori, Yasuyuki Ishii, Osami Kanagawa, Hiroshi Kawamoto, Kazuya Kawano, Haruhiko Koseki, Masato Kubo, Ai Kurita-Miki, Tomohiro Kurosaki, Kyoko Masuda, Mitsumasa Nakata, Keisuke Oboki, Hiroshi Ohno, Mariko Okamoto, Yoshimichi Okayama, Jiyang O-Wang, Hirohisa Saito, Takashi Saito, Machie Sakuma, Katsuaki Sato, Kaori Sato, Ken-Ichiro Seino, Ruka Setoguchi, Yuki Tamura, Masato Tanaka, Masaru Taniguchi, Ichiro Taniuchi, Annabelle Teng, Takeshi Watanabe, Hiroshi Watarai, Sho Yamasaki, Osamu Ohara
BIOINFORMATICS, 23, 21, 2934, 2941, 2007年11月, ［査読有り］
英語, 研究論文（学術雑誌） - Mechanism of NKT cell-mediated transplant tolerance
X. Jiang, S. Kojo, M. Harada, N. Ohkohchi, M. Taniguchi, K.-I. Seino
AMERICAN JOURNAL OF TRANSPLANTATION, 7, 6, 1482, 1490, 2007年06月, ［査読有り］
英語, 研究論文（学術雑誌） - Innate Immunity: NKT Cells
K. I. Seino, M. Taniguchi
Comprehensive Glycoscience: From Chemistry to Systems Biology, 4-4, 9, 16, Elsevier, 2007年01月01日, ［査読有り］
英語, 論文集(書籍)内論文 - Differential role of thymic stromal lymphopoietin in the induction of airway hyperreactivity and Th2 immune response in antigen-induced asthma with respect to natural killer T cell function
Yuko Nagata, Hajime Kamijuku, Masaru Taniguchi, Steven Ziegler, Ken-ichiro Seino
INTERNATIONAL ARCHIVES OF ALLERGY AND IMMUNOLOGY, 144, 4, 305, 314, 2007年, ［査読有り］
英語, 研究論文（学術雑誌） - Hyporesponsiveness to natural killer T-cell ligand alpha-galactosylceramide in cancer-bearing state mediated by CD11b(+) Gr-1(+) cells producing nitric oxide
Kazuhiko Yanagisawa, Mark A. Exley, Xiaofeng Jiang, Nobuhiro Ohkochi, Masaru Taniguchi, Ken-ichiro Seino
CANCER RESEARCH, 66, 23, 11441, 11446, 2006年12月, ［査読有り］
英語, 研究論文（学術雑誌） - IL-21-induced B epsilon cell apoptosis mediated by natural killer T cells suppresses IgE responses
Michishige Harada, Kumiko Magara-Koyanagi, Hiroshi Watarai, Yuko Nagata, Yasuyuki Ishii, Satoshi Kojo, Shigetoshi Horiguchi, Yoshitaka Okamoto, Toshinori Nakayama, Nobutaka Suzuki, Wen-Chen Yeh, Shizuo Akira, Hiroshi Kitamura, Osamu Ohara, Ken-ichiro Seino, Masaru Taniguchi
JOURNAL OF EXPERIMENTAL MEDICINE, 203, 13, 2929, 2937, 2006年12月, ［査読有り］
英語, 研究論文（学術雑誌） - Natural killer T cell-mediated antitumor immune responses and their clinical applications
Ken-ichiro Seino, Shinichiro Motohashi, Takehiko Fujisawa, Toshinori Nakayama, Masaru Taniguchi
CANCER SCIENCE, 97, 9, 807, 812, 2006年09月, ［査読有り］
英語 - CD1d-restricted NKT cell activation enhanced homeostatic proliferation of CD8(+) T cells in a manner dependent on IL-4
Naoko Ueda, Hiroko Kuki, Daisuke Kamimura, Shinichiro Sawa, Kenichiro Seino, Takuya Tashiro, Ken-ichi Fushuku, Masaru Taniguchi, Toshio Hirano, Masaaki Murakami
INTERNATIONAL IMMUNOLOGY, 18, 9, 1397, 1404, 2006年09月, ［査読有り］
英語, 研究論文（学術雑誌） - The importance of CD25(+)CD4(+) regulatory T cells in mouse hepatic allograft tolerance
Jiang, X, M Morita, A Sugioka, M Harada, S Kojo, H Wakao, H Watarai, N Ohkohchi, M Taniguchi, KI Seino
LIVER TRANSPLANTATION, 12, 7, 1112, 1118, 2006年07月, ［査読有り］
英語, 研究論文（学術雑誌） - Regulatory dendritic cells act as regulators of acute lethal systemic inflammatory response
S Fujita, K Seino, K Sato, Y Sato, K Eizumi, N Yamashita, M Taniguchi, K Sato
BLOOD, 107, 9, 3656, 3664, 2006年05月, ［査読有り］
英語, 研究論文（学術雑誌） - Indications for surgery in intestinal Behçet's disease.
Kurata M, Nozue M, Seino K, Murata H, Sumita T, Katashi F
Hepato-gastroenterology, 53, 67, 60, 63, 2006年01月, ［査読有り］
英語, 研究論文（学術雑誌） - Functionally distinct NKT cell subsets and subtypes
K Seino, M Taniguchi
JOURNAL OF EXPERIMENTAL MEDICINE, 202, 12, 1623, 1626, 2005年12月, ［査読有り］
英語 - Suppression of IgE antibody responses by NKT cells-mechanisms of NKT cell-mediated regulatory function
Satoshi Kojo, Michishige Harada, Ken-ichiro Seino, Masaru Taniguchi
International Congress Series, 1285, 179, 183, 2005年11月, ［査読有り］
英語, 研究論文（学術雑誌） - Induction of regulatory properties in dendritic cells by V alpha 14 NKT cells
S Kojo, K Seino, M Harada, H Watarai, H Wakao, T Uchida, T Nakayama, M Taniguchi
JOURNAL OF IMMUNOLOGY, 175, 6, 3648, 3655, 2005年09月, ［査読有り］
英語, 研究論文（学術雑誌） - Cutting edge: Critical role of CXCL16/CXCR6 in NKT cell trafficking in allograft tolerance
XF Jiang, T Shimaoka, S Kojo, M Harada, H Watarai, H Wakao, N Ohkohchi, S Yonehara, M Taniguchi, K Seino
JOURNAL OF IMMUNOLOGY, 175, 4, 2051, 2055, 2005年08月, ［査読有り］
英語, 研究論文（学術雑誌） - Renal allograft rejection is prevented by adoptive transfer of anergic T cells in nonhuman primates
H Bashuda, M Kimikawa, K Seino, Y Kato, F Ono, A Shimizu, H Yagita, S Teraoka, K Okumura
JOURNAL OF CLINICAL INVESTIGATION, 115, 7, 1896, 1902, 2005年07月, ［査読有り］
英語, 研究論文（学術雑誌） - V alpha 14 NKT cell-mediated anti-tumor responses and their clinical application
K Seino, S Fujii, M Harada, S Motohashi, T Nakayama, T Fujisawa, M Taniguchi
SPRINGER SEMINARS IN IMMUNOPATHOLOGY, 27, 1, 65, 74, 2005年06月, ［査読有り］
英語, 研究論文（学術雑誌） - Generation of cloned mice by direct nuclear transfer from natural killer T cells
K Inoue, H Wakao, N Ogonuki, H Miki, KI Seino, R Nambu-Wakao, S Noda, H Miyoshi, H Koseki, M Taniguchi, A Ogura
CURRENT BIOLOGY, 15, 12, 1114, 1118, 2005年06月, ［査読有り］
英語, 研究論文（学術雑誌） - Effect of E6060 [4-{5-[7-Fluoro-4-(trifluoromethyl)benzo[b]furan-2-yl]-1H-2-pyrrolyl}benzoic acid], a novel subtype-selective retinoid, on lupus-like nephritis in female (NZBxNZW)F1 mice
T Yamauchi, A Ishibashi, K Shikata, N Tokuhara, K Seino, S Kobayashi, M Nagai
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 312, 3, 938, 944, 2005年03月, ［査読有り］
英語, 研究論文（学術雑誌） - NKT cells: A regulator in both innate and acquired immunity
Ken-Ichiro Seino, Masaru Taniguchi
Current Medicinal Chemistry: Anti-Inflammatory and Anti-Allergy Agents, 4, 1, 59, 64, 2005年02月, ［査読有り］
英語 - Functional roles of NKT cell in the immune system
K Seino, M Taniguchi
FRONTIERS IN BIOSCIENCE, 9, 2577, 2587, 2004年09月
英語, 研究論文（学術雑誌） - Role of a NK receptor, KLRE-1, in bone marrow allograft rejection: analysis with KLRE-1-deficient mice
E Shimizu, J Koike, H Wakao, K Seino, H Koseki, T Kakiuchi, T Nakayama, M Taniguchi
BLOOD, 104, 3, 781, 783, 2004年08月, ［査読有り］
英語, 研究論文（学術雑誌） - Prevention of acute and chronic allograft rejection by a novel retinoic acid receptor-alpha-selective agonist
K Seino, T Yamauchi, K Shikata, S Kobayashi, M Nagai, M Taniguchi, K Fukao
INTERNATIONAL IMMUNOLOGY, 16, 5, 665, 673, 2004年05月, ［査読有り］
英語, 研究論文（学術雑誌） - NKT cells are relatively resistant to apoptosis
K Seino, M Harada, M Taniguchi
TRENDS IN IMMUNOLOGY, 25, 5, 219, 221, 2004年05月, ［査読有り］
英語, 研究論文（学術雑誌） - Impaired IFN-γ production of V_α24 NKT cells in non-remitting sarcoidosis
KOBAYASHI Seiichiro, KANEKO Yoshikatsu, SEINO Ken-ichiro, YAMADA Yoshihito, MOTOHASHI Shinichiro, KOIKE Junzo, SUGAYA Kaoru, KURIYAMA Takayuki, ASANO Shigetaka, TSUDA Tomiyasu, WAKAO Hiroshi, HARADA Michishige, KOJO Satoshi, NAKAYAMA Toshinori, TANIGUCHI Masaru
International immunology, 16, 2, 215, 222, 2004年02月
英語, 研究論文（学術雑誌） - Down-regulation of the invariant Vα14 antigen receptor in NKT cells upon activation
HARADA Michishige, SEINO Ken-ichiro, WAKAO Hiroshi, SAKATA Sakura, ISHIZUKA Yuko, ITO Toshihiro, KOJO Satoshi, NAKAYAMA Toshinori, TANIGUCHI Masaru
International immunology, 16, 2, 241, 247, 2004年02月
英語, 研究論文（学術雑誌） - Down-regulation of the invariant V alpha 14 antigen receptor in NKT cells upon activation
M Harada, K Seino, H Wakao, S Sakata, Y Ishizuka, T Ito, S Kojo, T Nakayama, M Taniguchi
INTERNATIONAL IMMUNOLOGY, 16, 2, 241, 247, 2004年02月
英語, 研究論文（学術雑誌） - Impaired IFN-gamma production of V(alpha)24NKT cells in non-remitting sarcoidosis
S Kobayashi, Y Kaneko, K Seino, Y Yamada, S Motohashi, J Koike, K Sugaya, T Kuriyama, S Asano, T Tsuda, H Wakao, M Harada, S Kojo, T Nakayama, M Taniguchi
INTERNATIONAL IMMUNOLOGY, 16, 2, 215, 222, 2004年02月, ［査読有り］
英語, 研究論文（学術雑誌） - Bone marrow allograft rejection mediated by a novel murine NK receptor, NKG2I
J Koike, H Wakao, Y Ishizuka, T Sato, M Hamaoki, K Seino, H Koseki, T Nakayama, M Taniguchi
JOURNAL OF EXPERIMENTAL MEDICINE, 199, 1, 137, 143, 2004年01月, ［査読有り］
英語, 研究論文（学術雑誌） - The NKT cell system: bridging innate and acquired immunity
M Taniguchi, K Seino, T Nakayama
NATURE IMMUNOLOGY, 4, 12, 1164, 1165, 2003年12月, ［査読有り］
英語 - Auxiliary partial orthotopic liver transplantation for fulminant hepatitis: Regeneration of the diseased native liver in a pig model
S Ishiguro, Y Takada, M Gu, K Fukunaga, H Taniguchi, K Seino, T Kawamoto, K Yuzawa, M Otsuka, T Todoroki, K Fukao
TRANSPLANTATION, 75, 11, 1901, 1904, 2003年06月, ［査読有り］
英語, 研究論文（学術雑誌） - Impaired proliferative response of V alpha 24 NKT cells from cancer patients against alpha-galactosylceramide
K Yanagisawa, K Seino, Y Ishikawa, M Nozue, T Todoroki, K Fukao
JOURNAL OF IMMUNOLOGY, 168, 12, 6494, 6499, 2002年06月, ［査読有り］
英語, 研究論文（学術雑誌） - Role of Fas/FasL pathway in the activation of infiltrating cells in murine acute myocarditis caused by Coxsackievirus B3
Y Seko, N Kayagaki, K Seino, H Yagita, K Okumura, R Nagai
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 39, 8, 1399, 1403, 2002年04月, ［査読有り］
英語, 研究論文（学術雑誌） - Effect of a novel potent cytokine suppressor on toxic liver syndrome in the pig treated by auxiliary partial orthotopic liver transplantation for fatal fulminant hepatic failure
S Ishiguro, Y Takada, K Fukunaga, Jiang, X, H Taniguchi, K Seino, K Yuzawa, M Otsuka, T Todoroki, K Fukao
PROCEEDINGS OF THE 37TH CONGRESS OF THE EUROPEAN SOCIETY FOR SURGICAL RESEARCH, 235, 237, 2002年, ［査読有り］
英語, 研究論文（国際会議プロシーディングス） - Treatment of advanced colorectal adenocarcinoma with weekly high-dose l-leucovorin and 5-fluorouracil
M Nozue, N Isaka, T Maruyama, T Kawamoto, K Seino, H Tanagichi, K Fukao
ONCOLOGY REPORTS, 9, 1, 93, 96, 2002年01月, ［査読有り］
英語, 研究論文（学術雑誌） - Treatment and prognosis in colorectal cancer patients with bone metastasis
M Nozue, Y Oshiro, M Kurata, K Seino, N Koike, T Kawamoto, H Taniguchi, T Todoroki, K Fukao
ONCOLOGY REPORTS, 9, 1, 109, 112, 2002年01月, ［査読有り］
英語, 研究論文（学術雑誌） - Transition and improvement in surgical treatment for rectal cancer during the last 21 years in our department
Y Oshima, M Nozue, H Taniguchi, KI Seino, N Koike, T Kawamoto, T Todoroki, K Fukao
INTERNATIONAL JOURNAL OF ONCOLOGY, 19, 6, 1283, 1286, 2001年12月, ［査読有り］
英語, 研究論文（学術雑誌） - Protection against Fas-mediated and tumor necrosis factor receptor 1-mediated liver injury by blockade of FADD without loss of nuclear factor-kappa B activation
K Seino, Y Setoguchi, T Ogino, N Kayagaki, H Akiba, H Nakano, H Taniguchi, Y Takada, K Yuzawa, T Todoroki, Y Fukuchi, H Yagita, K Okumura, K Fukao
ANNALS OF SURGERY, 234, 5, 681, 688, 2001年11月, ［査読有り］
英語, 研究論文（学術雑誌） - Living donor with type IV-A choledochal cyst in liver transplantation
Y Takada, T Hori, K Yuzawa, K Seino, H Taniguchi, M Otsuka, M Kaneko, K Fukao
TRANSPLANTATION, 72, 3, 551, 552, 2001年08月, ［査読有り］
英語 - Increased intracranial pressure in a porcine model of fulminant hepatic failure using amatoxin and endotoxin
Y Takada, S Ishiguro, K Fukunaga, M Gu, H Taniguchi, KI Seino, K Yuzawa, M Otsuka, T Todoroki, K Fukao
JOURNAL OF HEPATOLOGY, 34, 6, 825, 831, 2001年06月, ［査読有り］
英語, 研究論文（学術雑誌） - Role of platelet-activating factor in hepatectomy with Pringle's maneuver
M Gu, Y Takada, K Fukunaga, S Ishiguro, H Taniguchi, K Seino, K Yuzawa, M Otsuka, T Todoroki, K Fukao
JOURNAL OF SURGICAL RESEARCH, 96, 2, 233, 238, 2001年04月, ［査読有り］
英語, 研究論文（学術雑誌） - Requirement for natural killer T (NKT) cells in the induction of allograft tolerance
K Seino, K Fukao, K Muramoto, K Yanagisawa, Y Takada, S Kakuta, Y Iwakura, L Van Kaer, K Takeda, T Nakayama, M Taniguchi, H Bashuda, H Yagita, K Okumura
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 98, 5, 2577, 2581, 2001年02月
英語, 研究論文（学術雑誌） - The effect of alpha-galactosylceramide upon allogenic rejection
K Seino, K Yanagisawa, H Taniguchi, Y Takada, K Yuzawa, M Otsuka, K Fukao
TRANSPLANTATION PROCEEDINGS, 33, 1-2, 437, 438, 2001年02月, ［査読有り］
英語, 研究論文（学術雑誌） - Improvement of graft function without donor pretreatment in liver transplantation from non-heart-heating donors
M Gu, Y Takada, K Fukunaga, S Ishiguro, K Seino, H Taniguchi, K Yuzawa, M Otsuka, T Todoroki, K Fukao
TRANSPLANTATION PROCEEDINGS, 33, 1-2, 837, 838, 2001年02月, ［査読有り］
英語, 研究論文（学術雑誌） - Hepatic resection for metastatic tumors from noncolorectal carcinoma
Y Takada, M Otsuka, K Seino, H Taniguchi, N Koike, T Kawamoto, K Koda, S Adachi, K Yuzawa, M Nozue, T Todoroki, K Fukao
HEPATO-GASTROENTEROLOGY, 48, 37, 83, 86, 2001年01月, ［査読有り］
英語, 研究論文（学術雑誌） - Idiopathic calcifying pancreatitis in a Japanese pediatric patient
K Seino, Nishimori, I, Y Nagai, H Inoue, Y Takada, S Adachi, T Todoroki, K Fukao
JOURNAL OF GASTROENTEROLOGY, 35, 12, 941, 944, 2000年12月, ［査読有り］
英語, 研究論文（学術雑誌） - Peri- and postoperative kinetics of endothelin-1/big endothelin-1 and effects of endothelin antagonist in porcine liver transplantation from non-heart-beating donors
K Fukunaga, Y Takada, M Gu, S Ishiguro, K Seino, H Taniguchi, K Yuzawa, M Otsuka, K Goto, K Fukao
TRANSPLANTATION PROCEEDINGS, 32, 7, 1647, 1649, 2000年11月, ［査読有り］
英語, 研究論文（学術雑誌） - Long-term graft survival of living-related kidneys after donor-specific transfusion
M Otsuka, K Yuzawa, Y Takada, H Taniguchi, K Fukunaga, K Seino, T Todoroki, K Fukao
TRANSPLANTATION PROCEEDINGS, 32, 7, 1741, 1742, 2000年11月, ［査読有り］
英語, 研究論文（学術雑誌） - Inhibition of CD95 ligand-mediated inflammation
K Seino, T Tun, N Ohshima, H Hamada, K Yoshino, S Ikeda, K Fukunaga, H Taniguchi, Y Takada, K Yuzawa, M Otsuka, T Todoroki, K Fukao
TRANSPLANTATION PROCEEDINGS, 32, 7, 2038, 2039, 2000年11月, ［査読有り］
英語, 研究論文（学術雑誌） - Porcine model of fulminant hepatic failure treated by liver transplantation
Y Takada, K Fukunaga, G Gei, S Ishiguro, H Taniguchi, K Seino, Y Yuzawa, M Otsuka, K Fukao
TRANSPLANTATION PROCEEDINGS, 32, 7, 2243, 2244, 2000年11月, ［査読有り］
英語, 研究論文（学術雑誌） - Clonal colony formation of hepatic stem/progenitor cells enhanced by embryonic fibroblast conditioning medium
A Suzuki, H Taniguchi, YW Zheng, Y Takada, K Fukunaga, K Seino, K Yazawa, M Otsuka, K Fukao, H Nakauchi
TRANSPLANTATION PROCEEDINGS, 32, 7, 2328, 2330, 2000年11月, ［査読有り］
英語, 研究論文（学術雑誌） - Proliferative and functional ability of transplanted murine neonatal hepatocytes in adult livers
A Suzuki, H Taniguchi, YW Zheng, Y Takada, K Fukunaga, K Seino, K Yazawa, M Otsuka, A Yoshiki, M Kusakabe, K Fukao, H Nakauchi
TRANSPLANTATION PROCEEDINGS, 32, 7, 2370, 2371, 2000年11月, ［査読有り］
英語, 研究論文（学術雑誌） - Effects of combined growth factors on clonal growth and albumin secretion of murine fetal hepatocytes in low density culture
YW Zheng, H Taniguchi, A Suzuki, Y Takada, K Fukunaga, K Seino, K Yuzawa, M Otsuka, K Fukao, H Nakauchi
TRANSPLANTATION PROCEEDINGS, 32, 7, 2372, 2373, 2000年11月, ［査読有り］
英語, 研究論文（学術雑誌） - Effects of four extracellular matrices associated with growth factors on clonal culture and proliferation of murine fetal hepatocytes
YW Zheng, H Taniguchi, A Suzuki, Y Takada, K Fukunaga, K Seino, K Yuzawa, M Otsuka, K Fukao, H Nakauchi
TRANSPLANTATION PROCEEDINGS, 32, 7, 2498, 2499, 2000年11月, ［査読有り］
英語, 研究論文（学術雑誌） - Pharmacologic graft protection without donor pretreatment in liver transplantation from non-heart-beating donors
M Gu, Y Takada, K Fukunaga, S Ishiguro, H Taniguchi, K Seino, K Yuzawa, M Otsuka, T Todoroki, K Fukao
TRANSPLANTATION, 70, 7, 1021, 1025, 2000年10月, ［査読有り］
英語, 研究論文（学術雑誌） - Clonogenic colony-forming ability of flow cytometrically isolated hepatic progenitor cells in the murine fetal liver
H Taniguchi, R Kondo, A Suzuki, YW Zheng, Y Takada, K Fukunaga, K Seino, K Yuzawa, M Otsuka, K Fukao, H Nakauchi
CELL TRANSPLANTATION, 9, 5, 697, 700, 2000年09月, ［査読有り］
英語, 研究論文（学術雑誌） - Improvement of allograft viability with organs procured from non-heart-beating donors in porcine liver transplantation
Y Takada, K Fukunaga, M Gu, S Ishiguro, H Taniguchi, K Seino, K Yuzawa, M Otsuka, K Fukao
TRANSPLANTATION PROCEEDINGS, 32, 2, 277, 278, 2000年03月, ［査読有り］
英語, 研究論文（学術雑誌） - Prolongation of mouse skin allograft survival by novel agonists selective for retinoic acid receptor-alpha
K Seino, T Yamauchi, A Ishibashi, N Tokuhara, S Kobayashi, K Fukunaga, H Taniguchi, Y Takada, K Yuzawa, M Otsuka, T Todoroki, K Fukao
TRANSPLANTATION PROCEEDINGS, 32, 2, 257, 258, 2000年03月, ［査読有り］
英語, 研究論文（学術雑誌） - Usefulness of flow-cytometric cell sorting for enrichment of hepatic stem and progenitor cells in the liver
H Taniguchi, A Suzuki, Y Zheng, R Kondo, Y Takada, K Fukunaga, K Seino, K Yuzawa, M Otsuka, K Fukao, H Nakauchi
TRANSPLANTATION PROCEEDINGS, 32, 2, 249, 251, 2000年03月, ［査読有り］
英語, 研究論文（学術雑誌） - Attempts to reveal the mechanism of CD95-ligand-mediated inflammation
K Seino, T Ogino, K Fukunaga, H Taniguchi, Y Takada, K Yuzawa, M Otsuka, H Yagita, K Okumura, K Fukao
TRANSPLANTATION PROCEEDINGS, 31, 5, 1942, 1943, 1999年08月, ［査読有り］
英語, 研究論文（学術雑誌） - An endothelin receptor antagonist ameliorates injuries of sinusoid lining cells in porcine liver transplantation
K Fukunaga, Y Takada, G Mei, H Taniguchi, K Seino, K Yuzawa, M Otsuka, T Todoroki, K Goto, K Fukao
AMERICAN JOURNAL OF SURGERY, 178, 1, 64, 68, 1999年07月, ［査読有り］
英語, 研究論文（学術雑誌） - Soluble forms of CD95 and CD95 ligand after living related liver transplantation
K Seino, N Kayagaki, N Yamaguchi, Y Takada, S Uyama, T Kiuchi, K Tanaka, H Yagita, K Okumura, K Fukao
TRANSPLANTATION, 67, 4, 634, 636, 1999年02月, ［査読有り］
英語, 研究論文（学術雑誌） - Evidence for the presence of hepatic stem cells in the murine fetal liver
H Taniguchi, R Kondo, A Suzuki, Y Zheng, S Ito, Y Takada, K Fukunaga, K Seino, K Yuzawa, M Otsuka, K Fukao, A Yoshiki, M Kusakabe, H Nakauchi
TRANSPLANTATION PROCEEDINGS, 31, 1-2, 454, 454, 1999年02月, ［査読有り］
英語, 研究論文（学術雑誌） - Biological factors that affect CD95 ligand-mediated inflammation
K Seino, T Ogino, ST Ju, H Hamada, H Yagita, K Okumura, K Fukao
TRANSPLANTATION PROCEEDINGS, 31, 1-2, 893, 895, 1999年02月, ［査読有り］
英語, 研究論文（学術雑誌） - Endothelin antagonist treatment for successful liver transplantation from non-heart-beating donors
K Fukunaga, Y Takada, H Taniguchi, G Mei, K Seino, K Yuzawa, M Otsuka, T Todoroki, K Goto, K Fukao
TRANSPLANTATION, 67, 2, 328, 332, 1999年01月, ［査読有り］
英語, 研究論文（学術雑誌） - Cutting edge: Chemotactic activity of soluble Fas ligand against phagocytes
K Seino, K Iwabuchi, N Kayagaki, R Miyata, Nagaoka, I, A Matsuzawa, K Fukao, H Yagita, K Okumura
JOURNAL OF IMMUNOLOGY, 161, 9, 4484, 4488, 1998年11月, ［査読有り］
英語, 研究論文（学術雑誌） - Can expression of CD95 (Fas/APO-1) ligand on grafts or tumor cells prevent their rejection?
J Allison, K Seino, H Yagita
SPRINGER SEMINARS IN IMMUNOPATHOLOGY, 19, 3, 311, 322, 1998年, ［査読有り］
英語, 研究論文（学術雑誌） - Contribution of Fas ligand to T cell-mediated hepatic injury in mice
KI Seino, N Kayagaki, K Takeda, K Fukao, K Okumura, H Yagita
GASTROENTEROLOGY, 113, 4, 1315, 1322, 1997年10月, ［査読有り］
英語, 研究論文（学術雑誌） - Transplantation of CD95 ligand-expressing grafts - Influence of transplantation site and difficulty in protecting allo- and xenografts
K Seino, N Kayagaki, N Tsukada, K Fukao, H Yagita, K Okumura
TRANSPLANTATION, 64, 7, 1050, 1054, 1997年10月, ［査読有り］
英語, 研究論文（学術雑誌） - Immunoregulation via adhesion molecules in allogenic and xenogenic hepatocyte transplantation to Nagase's analbuminemic rats
H Horimoto, M Nozawa, N Kokudo, M Nakao, S Takahashi, M Miyasaka, K Seino, H Yagita, K Okumura
CELL TRANSPLANTATION, 6, 5, 535, 536, 1997年09月, ［査読有り］
英語, 研究論文（学術雑誌） - Antitumor effect of locally produced CD95 ligand
KI Seino, N Kayagaki, K Okumura, H Yagita
NATURE MEDICINE, 3, 2, 165, 170, 1997年02月, ［査読有り］
英語, 研究論文（学術雑誌） - Rejection of Fas ligand-expressing grafts
K Seino, N Kayagaki, K Fukao, K Okumura, H Yagita
TRANSPLANTATION PROCEEDINGS, 29, 1-2, 1092, 1093, 1997年02月, ［査読有り］
英語, 研究論文（学術雑誌） - Lack of cognate help by CD4(+) T cells and anergy of CD8(+) T cells are the principal mechanisms for anti-leukocyte function-associated antigen-1 intercellular adhesion molecule-1-induced cardiac allograft tolerance
H Bashuda, K Seino, C Ra, H Yagita, K Okumura
TRANSPLANTATION, 63, 1, 113, 118, 1997年01月, ［査読有り］
英語, 研究論文（学術雑誌） - Contribution of Fas ligand to cardiac allograft rejection
K Seino, N Kayagaki, H Bashuda, K Okumura, H Yagita
INTERNATIONAL IMMUNOLOGY, 8, 9, 1347, 1354, 1996年09月, ［査読有り］
英語, 研究論文（学術雑誌） - Topical immunosuppression in skin grafting with FK 506 ointment
K Yuzawa, H Taniguchi, K Seino, M Otsuka, K Fukao
TRANSPLANTATION PROCEEDINGS, 28, 3, 1387, 1389, 1996年06月, ［査読有り］
英語, 研究論文（学術雑誌） - Synergistic effects of mycophenolate mofetil (MMF, RS-61443) and anti-LFA-1/ICAM-1 monoclonal antibodies on the prolongation of heart allograft survival in rats
K Takazawa, Y Hosoda, H Bashuda, K Seino, H Yagita, T Tamatani, M Miyasaka, K Okumura
TRANSPLANTATION PROCEEDINGS, 28, 3, 1980, 1981, 1996年06月, ［査読有り］
英語, 研究論文（学術雑誌） - Specific acceptance of cardiac allografts after treatment with antibodies to CD80 and CD86 in mice
H Bashuda, K Seino, M Kano, K Sato, M Azuma, H Yagita, K Okumura
TRANSPLANTATION PROCEEDINGS, 28, 2, 1039, 1041, 1996年04月, ［査読有り］
英語, 研究論文（学術雑誌） - CD95 ligand in graft rejection - Reply
RC Duke, A Franzusoff, D Bellgrau
NATURE, 379, 6567, 682, 683, 1996年02月, ［査読有り］
英語 - 接着分子の制御による末梢性トレランス
場集 田寿, 清野 研一郎, 狩野 基, 佐藤 健志, 八木田 秀雄, 奥村 康
日本臨床免疫学会会誌 = Japanese journal of clinical immunology, 18, 6, 679, 679, 日本臨床免疫学会, 1995年12月31日
日本語 - CD86 (B70/B7-2) ON ENDOTHELIAL-CELLS CO-STIMULATES ALLOGENEIC CD4(+) T-CELLS
K SEINO, M AZUMA, H BASHUDA, K FUKAO, T YAGITA, K OKUMURA
INTERNATIONAL IMMUNOLOGY, 7, 8, 1331, 1337, 1995年08月, ［査読有り］
英語, 研究論文（学術雑誌）
その他活動・業績
- IL-34, the rationale for its expression in physiological and pathological conditions
Ryo Otsuka, Haruka Wada, Ken-ichiro Seino, SEMINARS IN IMMUNOLOGY, 54, 2021年04月
英語, 書評論文,書評,文献紹介等 - IL-34が大腸がんに与える影響の解析
小林拓斗, 韓ナヌミ, 和田はるか, 宮城洋平, 醍醐弥太郎, 醍醐弥太郎, 醍醐弥太郎, 清野研一郎, 日本インターフェロン・サイトカイン学会学術集会抄録集, 85th (CD-ROM), 2021年 - ATLLにおけるM-CSFR発現とM-CSFR阻害剤の有効性(Potential anti-lymphoma effect of M-CSFR inhibitor in adult T-cell leukemia/lymphoma)
菰原 義弘, Muhammad Baghdadi, 清野 研一郎, 奥野 豊, 野坂 生郷, 松岡 雅雄, 日本癌学会総会記事, 78回, P, 1014, 2019年09月
日本癌学会, 英語 - 卵巣癌転移におけるインターロイキン-34の潜在的役割
羽馬直希, バグダーディ ムハンマド, 小林拓斗, 梅山悠伊, 韓ナヌミ, 和田はるか, 清野研一郎, 日本免疫治療学会学術集会プログラム・抄録集, 16th, 2019年 - Interleukin-34, がんの治療標的としての可能性
ムハンマド・バグダーディー, 清野研一郎, 臨床免疫・アレルギー科, 70, 4, 422, 428, 2018年10月, ［査読有り］, ［招待有り］
日本語, 記事・総説・解説・論説等（学術雑誌） - 再生医療時代におけるあらたな移植免疫制御 (特集 iPS細胞技術を駆使したがん,感染症のあらたな制御)
大塚 亮, 清野 研一郎, 医学のあゆみ, 263, 11, 927, 931, 2017年12月23日
医歯薬出版, 日本語 - IL-34 as a prognostic biomarker and a therapeutic target in cancer
Muhammad Baghdadi, Ken-ichiro Seino, CYTOKINE, 100, 58, 58, 2017年12月
英語, 研究発表ペーパー・要旨（国際会議） - 肺がんにおいてIL-34とM-CSFの共発現が予後に及ぼす影響(Prognostic significance of IL-34 and M-CSF co-expression in lung cancers)
遠藤 拓, Baghdadi Muhammad, 石川 浩三, 和田 はるか, 清野 研一郎, 鈴木 直, 宮城 洋平, 横瀬 智之, 高野 淳, 醍醐 弥太郎, 日本がん免疫学会総会プログラム・抄録集, 21回, 120, 120, 2017年06月
日本がん免疫学会, 英語 - 放射線刺激により誘発されるインターロイキン34の放射線治療抵抗性における潜在的役割について
遠藤 拓, Muhammad Baghdadi, 石川 浩三, 江澤 永倫子, 梅山 悠伊, 和田 はるか, 鈴木 直, 清野 研一郎, 聖マリアンナ医科大学雑誌, 45, 3, 173, 183, 2017年
<p>放射線療法は手術療法，化学療法と並び，三大がん治療法に挙げられているが，一方で腫瘍再発の起点となる放射線耐性が課題として残されている。がん細胞の薬剤耐性獲得機序には，がん細胞側の内因性機序と腫瘍微小環境（TME）内の骨髄系細胞との外因性機序とが説明されている。近年発見されたInterleukin 34（IL-34）は，マクロファージコロニー刺激因子（M-CSF）と受容体を共有し同様の生理活性を示すが，腫瘍を含む様々な病態への独自の関与が報告されている。最近我々は，肺癌細胞の抗がん剤耐性化にIL-34が上記の内因性，外因性機序の両者に関与することを示した。本研究では，その先行研究を基に，放射線治療適応である前立腺癌および直腸癌細胞株を用いて，放射線の単回および反復照射下にIL-34およびM-CSFの発現変動を調べた。その結果，放射線単回照射では両者の発現誘導が認められたのに対し，反復照射ではIL-34のみが時間経過に伴い顕著な発現誘導を認めた。さらにその機序は抗がん剤刺激と同様にNF-kBを介した経路であることが阻害剤を用いて示された。このことから，長期の放射線ストレスにIL-34が誘導され放射線治療耐性へ関与する可能性が示唆される。今後はさらに放射線暴露によるIL-34のTMEへの作用を精査するとともに，放射線療法との併用としてIL-34標的治療の可能性について探索してゆく。</p>, 学校法人 聖マリアンナ医科大学医学会, 日本語 - 多能性幹細胞を用いた免疫寛容誘導
大塚 亮, 和田 はるか, バグダーディー ムハンマド, 辻 飛雄馬, 清野 研一郎, 移植, 52, 6, 489, 494, 2017年
<p>Induced pluripotent stem cell (iPSC) -based technologies provide new opportunities in regenerative medicine to generate grafts for transplantation. The banking of iPSCs from donors with homozygous HLA haplotypes is planned in Japan, aiming to reduce immune reaction. Even though HLA-homozygous iPSCs are used, immune suppression would be inevitable because of minor antigen mismatches. A couple of studies concerning such immunological issues have been reported, including gene modification and immune regulatory cell induction from PSCs. Meanwhile, our research group has recently examined the concept that the recipient immune response against PSC-derived graft can be regulated by administration of immunoregulatory cells generated from the same PSC. This therapeutic approach prolonged the survival of PSC-derived allograft by suppressing host T cell proliferation and antibody production by B cells.</p><p>iPSC-based technologies provide us numerous benefits; however, considering their safety from an immunological point of view should be of great importance for the development and clinical translation of this novel techniques.</p>, 一般社団法人 日本移植学会, 日本語 - IL-34と腫瘍
Baghdadi Muhammad, 遠藤 拓, 和田 はるか, 清野 研一郎, 臨床免疫・アレルギー科 = Clinical immunology & allergology, 67, 1, 88, 92, 2017年01月
科学評論社, 日本語 - オモロイ生き物の分子生物学 長寿・がん化耐性動物ハダカデバネズミiPS細胞の腫瘍化耐性機構の解明
宮脇 慎吾, 河村 佳見, 大岩 祐基, 清野 研一郎, 岡野 栄之, 三浦 恭子, 日本生化学会大会・日本分子生物学会年会合同大会講演要旨集, 88回・38回, [3W8, 1], 2015年12月
(公社)日本生化学会, 日本語 - Induction of iNOS Expressed Macrophages from Mouse iPS cells That Contribute to Prolong Same iPS Cells-Derived Graft Survival in Allogeneic Recipients
H. Sasaki, H. Wada, K. Morita, K. -I. Seino, N. Shinohara, AMERICAN JOURNAL OF TRANSPLANTATION, 15, 2015年05月
英語, 研究発表ペーパー・要旨（国際会議） - 移植における免疫制御の未来動向
清野 研一郎, 移植, 50, 1, 11, 15, 2015年
Transplantation has been developed based on the progress of immunosuppression. During the past half-century, various excellent immunosuppressants have been developed. Furthermore, the induction of immunological tolerance has been investigated to improve the outcome, and it has already been applied clinically. Turning our attention to the future, an age of cellular transplantation using pluripotent stem cells would be realistic. Even in this age, when other-derived pluripotent stem cells as the source of transplantation are used, the idea of immune regulation is important. The investigation of immune regulation using pluripotent stem cells has already been started., 一般社団法人 日本移植学会, 日本語 - Induction of Regulatory Macrophage-Like Cells From Mouse iPS Cells That Can Contribute to Suppress Allogeneic Immune Responses.
H. Sasaki, H. Wada, H. Kudo, K. Nonomura, K. Seino, TRANSPLANTATION, 98, 285, 285, 2014年07月
英語, 研究発表ペーパー・要旨（国際会議） - Induction of Regulatory Macrophage-Like Cells From Mouse iPS Cells That Can Contribute to Suppress Allogeneic Immune Responses.
H. Sasaki, H. Wada, H. Kudo, K. Nonomura, K. Seino, AMERICAN JOURNAL OF TRANSPLANTATION, 14, 285, 285, 2014年06月
英語, 研究発表ペーパー・要旨（国際会議） - SY-7-5 多能性幹細胞を用いた再生医療時代の免疫制御(SY シンポジウム,第113回日本外科学会定期学術集会)
清野 研一郎, 日本外科学会雑誌, 114, 2, 2013年03月05日
一般社団法人日本外科学会, 日本語 - B細胞から誘導したiPS細胞の樹立及び試験管内におけるリンパ球分化
和田 はるか, 香城 諭, 草間 千枝, 岡本 直樹, 佐藤 可野, 石塚 文平, 清野 研一郎, 北海道醫學雜誌 = Acta medica Hokkaidonensia, 87, 2, 2012年04月01日
日本語 - Induction of Donor Specific hyporesponsiveness by Adoptive Transfer of Ex Vivo Expanded Anergic Cells
I. Koyama, H. Bashuda, K. -I. Seino, J. Yagi, H. Fujii, I. Nakajima, S. Fuchinoue, K. Okumura, S. Teraoka, AMERICAN JOURNAL OF TRANSPLANTATION, 11, 77, 77, 2011年04月
英語, 研究発表ペーパー・要旨（国際会議） - 新しい再生医療へ向けた新規細胞の作製 : ガンマデルタAPCに関する研究
清野 研一郎, 第一三共生命科学研究振興財団研究報告集, 27, 0, 87, 91, 2011年
第一三共生命科学研究振興財団, 日本語 - NotchシグナルによるNK細胞の分化と機能制御 (特集 NK細胞・NKT細胞の機能制御分子)
和田 はるか, 清野 研一郎, 臨床免疫・アレルギー科, 53, 2, 126, 132, 2010年02月
科学評論社, 日本語 - Self-education by NK cells
Haruka Wada, Satoshi Kojo, Ken-Ichiro Seino, Immunotherapy, 1, 5, 738, 2009年09月
英語, 書評論文,書評,文献紹介等 - Adjuvant effect of IL-7 in vaccine-mediated cancer immunotherapy
Haruka Wada, Satoshi Kojo, Ken-Ichiro Seino, Immunotherapy, 1, 5, 738, 739, 2009年09月
英語, 書評論文,書評,文献紹介等 - Suppressor turns into helper
Haruka Wada, Satoshi Kojo, Ken-ichiro Seino, IMMUNOTHERAPY, 1, 5, 737, 737, 2009年09月
英語, その他 - K3-36 卵巣癌培養細胞中の癌幹細胞の存在と抗癌剤感受性との関連性(高得点演題15 腫瘍,高得点演題プログラム,第61回日本産科婦人科学会学術講演会)
小林 陽一, 清野 研一郎, 細沼 信示, 大原 樹, 鈴木 直, 木口 一成, 石塚 文平, 板持 広明, 紀川 純三, 礒西 成治, 菊池 義公, 日本産科婦人科學會雜誌, 61, 2, 655, 655, 2009年
日本産科婦人科学会, 日本語 - 19 ナチュラルキラー(NK)T細胞を活性化する新規糖脂質の創製(口頭発表の部)
田代 卓哉, 冨宿 賢一, 清野 研一郎, 渡会 浩志, 谷口 克, 森 謙治, 天然有機化合物討論会講演要旨集, 48, 0, 109, 114, 2006年
NKT cell is a potent producer of immunoregulatory cytokines. T cell receptor of NKT cell recognizes CD1d protein-α-galactosylceramide complex, and activated NKT cell can produce the both Th1 (immunostimulant) and Th2 (immunosuppressant)-types cytokines. KRN7000 (2), developed by Kirin Brewery Co. Ltd., is a derivative of natural α-galactosylceramide, agerasphins (main component is agelasphin-9b, 1). KRN7000 is a strong stimulant to NKT cells. However, it induces both Th1 and Th2-type cytokines production of NKT cell by single stimulation. The analogue OCH (3), possessing shorter alkyl chains as developed by Yamamura et al., induces predominant production of interleukin (IL)-4, a key cytokine of Th2 type, over Th1 type cytokines. The total amount of IL-4, produced by NKT cells by stimulation with OCH, however, was less than that in the case of 2. For improvement of this problem, we developed two kinds of new galactosylceramides. One of them is those possessing a ring structure on the sphingosine chain. This analogue was synthesized from the known epoxide 6. The selective reductive-epoxide opening reaction to 6 afforded alcohol 7 or 12. The four-membered ring part was constructed from alcohol 7, whereas alcohol 12 was converted to the five-membered ring part. The resulting products were converted to the corresponding galactosylceramides respectively. Another kind of the analogues (21) were those possessing sulfonamide chain instead of the acyl chain. Those analogues could be synthesized easily from the commercially available phytosphingosine (17). Both analogues could make complexes with CD1d, and induce NKT cells to produce Th1 type cytokine predominantly., 天然有機化合物討論会実行委員会, 日本語 - Preferential enhancement of immunosuppressive function of V alpha 14 NKT cells by liposome-encapsulated alpha-galactosylceramide
Y Ishii, R Nozawa, Y Takamoto, H Nishikawa, KI Seino, M Taniguchi, FASEB JOURNAL, 19, 4, A31, A31, 2005年03月
英語, 研究発表ペーパー・要旨（国際会議） - 活性化NKT細胞による寛容誘導性樹状細胞の誘導
香城諭, 清野研一郎, 原田通成, 渡会浩志, 若尾宏, 内田哲郎, 中山俊憲, 谷口克, 日本免疫学会総会・学術集会記録, 34, 336, 336, 2004年11月05日
(NPO)日本免疫学会, 日本語 - BCG投与による活性化Vα14 NKT細胞のIgE産生抑制
原田通成, 清野研一郎, 真柄久美子, 石井保之, 香城諭, 若尾宏, 渡会浩志, 中山俊憲, 谷口克, 日本免疫学会総会・学術集会記録, 34, 335, 2004年11月05日
日本語 - Prevention of acute and chronic allograft rejection by a novel retinoic acid receptor-alpha-selective agonist (vol 16, pg 665, 2004)
K Seino, T Yamauchi, K Shikata, S Kobayashi, M Nagai, M Taniguchi, K Fukao, INTERNATIONAL IMMUNOLOGY, 16, 7, 1053, 1053, 2004年07月
英語, その他 - Bone marrow allograft rejection mediated by the murine NK receptor NKG21/KLRE1 (vol 199, pg 137, 2004)
J Koike, H Wakao, Y Ishizuka, T Sato, M Hamaoki, K Seino, H Koseki, T Nakayama, M Taniguchi, JOURNAL OF EXPERIMENTAL MEDICINE, 199, 3, 435, 435, 2004年02月
英語, その他 - NKT細胞による樹状細胞を介した免疫制御機構の解析
香城諭, 清野研一郎, 原田通成, 渡会浩志, 石井保之, 石井崇太郎, 若尾宏, 中山俊憲, 谷口克, 日本免疫学会総会・学術集会記録, 33, 150, 2003年11月05日
日本語 - NKT細胞の活性化によるVα14受容体のdown-regulation
原田 通成, 清野 研一郎, 若尾 宏, 坂田 さくら, 伊藤 俊広, 香城 諭, 中山 俊憲, 谷口 克, 日本免疫学会総会・学術集会記録, 33, 151, 151, 2003年11月
(NPO)日本免疫学会, 日本語 - 担癌状態におけるNKT細胞低反応性のメカニズム
柳澤 和彦, 黒岩 憲二, 清野 研一郎, 谷口 克, 大河内 信弘, 日本外科学会雑誌, 104, 532, 532, 2003年04月30日
一般社団法人日本外科学会, 日本語 - 移植免疫寛容誘導におけるNKT細胞の役割
清野 研一郎, 村本 賢三, 谷口 克, 中山 俊憲, 場集田 寿, 竹田 和由, 八木田 秀雄, 奥村 康, 深尾 立, 日本免疫学会総会・学術集会記録, 30, 86, 86, 2000年11月
日本語 - PP1454 肺癌術後に血清AFPの高値を示し肝細胞癌との鑑別に難渋した巨大肝転移の一切除例
大城 幸雄, 榎本 剛史, 高田 泰次, 清野 研一郎, 谷口 英樹, 小池 直人, 幸田 圭史, 足立 信也, 大塚 雅昭, 轟 健, 深尾 立, 石川 成美, 飯島 達生, 日本消化器外科学会雑誌, 33, 7, 1258, 1258, 2000年07月01日
一般社団法人日本消化器外科学会, 日本語 - An endothelin receptor antagonist ameliorates injuries of sinusoid lining cells in porcine liver transplantation (vol 178, pg 64, 1999)
K Fukanaga, Y Takada, G Mei, H Taniguchi, K Seino, K Yuzawa, M Otsuka, T Todoroki, K Goto, K Fukao, AMERICAN JOURNAL OF SURGERY, 178, 5, 436, 436, 1999年11月
英語, その他 - 移植免疫におけるNKT細胞の役割
清野 研一郎, 村本 賢三, 谷口 克, 中山 俊憲, 八木田 秀雄, 奥村 康, 深尾 立, 日本免疫学会総会・学術集会記録, 29, 55, 55, 1999年10月
日本語 - FADD-dominant negative遺伝子導入によるFas Ligand及びTNF誘導性臓器障害の治療
清野 研一郎, 八木田 秀雄, 奥村 康, 深尾 立, 日本外科学会雑誌, 100, 臨増, 78, 78, 1999年02月
日本語 - 免疫寛容の誘導と維持における最先端 Fasリガンドの発現による免疫寛容誘導に関する研究
清野 研一郎, 八木田 秀雄, 奥村 康, 深尾 立, 移植, 33, 総会臨時, 125, 125, 1998年10月
日本語 - 皮膚移植拒絶におけるFas/FasLの役割
荻野 隆史, 清野 研一郎, 場集田 寿, 小端 哲二, 八木田 秀雄, 奥村 康, 森下 靖雄, 移植, 33, 総会臨時, 160, 160, 1998年10月
日本語 - CD95 ligand in graft rejection
H Yagita, K Seino, N Kayagaki, K Okumura, NATURE, 379, 6567, 682, 682, 1996年02月
英語, 速報，短報，研究ノート等（学術雑誌）
共同研究・競争的資金等の研究課題
- iPS細胞由来造血幹・前駆細胞（iHSPC）を用いた免疫制御法の開発
科学研究費助成事業
2022年04月01日 - 2025年03月31日
清野 研一郎, 和田 はるか
MHC適合マイナー抗原不一致のマウス皮膚移植モデルを用い、iPS細胞から作成した造血幹・前駆細胞（HSPC）の移入により拒絶反応を制御できるかどうか検討してきた。iPS細胞からHSPCを分化誘導させるためには、転写因子の遺伝子導入が必要であった。検討した結果、幹細胞の増殖に関与するLhx2並びにHoxB4の発現が有効であった。これらを発現させたHSPCを試験管内で誘導し、マウスに注射した。同種同系の場合はもちろん、前処置を施せばMHC適合マイナー抗原不一致のマウスにも生着することが判明した。同種同系の場合、20週目でのCD45キメラ率は4-5％、そのうちCD11b陽性細胞の割合は10-20％であった。アロの場合も、前処置をしっかり行えば同程度のキメラ率が得られた。このキメラ状態となったマウスにiPS細胞を同系統の皮膚を移植したところ、高効率で生着することが判明した。また、皮膚だけでなくiPS細胞そのものを移植した場合も奇形腫として生着することが判明した。メカニズムとしては、CD11b陽性Gr-1陽性のMDSC、またFoxP3陽性の制御性T細胞の増加が認められた。これらの結果から、再生医療において、iPS細胞由来HSPCを用いた免疫制御により免疫抑制剤なしの移植が可能であることが示された。さらに、完全アロの組み合わせにおいてもコスティミュラトリーシグナルの阻害を併用することにより、HSPCを用いた方法により皮膚移植編の生着が得られた。これらの結果から、iPS細胞由来HSPCを用いた免疫制御法は幅広く免疫疾患の治療に応用できることが示唆された。
日本学術振興会, 基盤研究(B), 北海道大学, 23K24105 - 自然免疫関連遺伝子を用いた新しい全細胞型がんワクチンの開発
科学研究費助成事業
2022年06月30日 - 2024年03月31日
清野 研一郎, 和田 はるか
近年、大きな注目を集めているがん免疫療法の中でも、がんワクチンは免疫系の持つ絶妙なパワーと特異性を利用することで、腫瘍の再発を予防できる可能性がある。具体的には、外科的に切除された腫瘍に基づく全腫瘍細胞ワクチン（WTCV）は、様々な腫瘍関連抗原を宿主免疫に暴露することにより、強固な抗腫瘍免疫応答を引き起こすと考えられてきた。しかし、ほとんどの腫瘍は、宿主免疫との継続的な相互作用によって免疫編集されているため、免疫原性はほとんどない。したがって、患者由来の非改変腫瘍に基づくWTCVを調製しても、腫瘍の発症を予防することはできない。したがって、効果的なWTCVのためには、腫瘍細胞の免疫原性を改善する必要がある。本研究では、腫瘍細胞内のインターフェロン制御因子7（Irf7）軸（Irf7とその下流因子を含む）が免疫原性を制御する上で重要であることを示した。実際、Irf7軸としてを増強したIrf7、Ifi44、Usp18を導入したWTCVは、放射線による腫瘍不活化後にワクチン接種すると、顕著な再発予防効果を発揮した。最も注目すべきは、Irf7、Ifi44、Usp18を導入したマウス大腸がん細胞のワクチン接種により、すべてのマウスでチャレンジド腫瘍の発生が阻止され、観察期間中の生存率が100％になったことである。さらに、ワクチン効果につながるメカニズムは、インターフェロン-γ産生B細胞によって媒介された。本研究は、免疫原性細胞死を検出するためのゴールドスタンダードであるin vivoワクチン接種実験を通じて、Irf7とその下流因子をがん細胞に導入することにより、免疫原性の低いがん細胞の特性を変換する、すなわち免疫原性を高めるための新規戦略を初めて実証した。この研究は、腫瘍の免疫原性を増強し、再発予防としてWTCVを使用する方法について新たな洞察を与えるものである。
日本学術振興会, 挑戦的研究(萌芽), 北海道大学, 22K19449 - 多発性骨髄腫の骨病変におけるIL-34の作用機序解明と治療応用に向けた研究
科学研究費助成事業
2017年04月01日 - 2020年03月31日
石川 浩三, 清野 研一郎
多発性骨髄腫（Multiple Myeloma : MM）は骨破壊病変を主徴候とする。CSF-1受容体の新規のリガンドであるIL-34と骨破壊病態の関与が近年注目されている。我々は、MMモデルマウスの実験系で、骨髄の炎症性サイトカインや間質細胞がMM細胞のIL-34発現を増強することを示した。またIL-34をknockdownしたところ破骨形成が阻害されることを示した。MM患者の骨髄検体においてCD138+細胞のIL-34発現性は様々であったが、破骨形成誘導能はIL-34中和抗体により抑制された。
以上からMM細胞に起因するIL-34はMM患者の骨破壊治療の有効な標的となる可能性が示唆される。
日本学術振興会, 基盤研究(C), 北海道大学, 17K09913 - iPS細胞を用いたアロの壁と時空間を超える免疫制御法に関する研究
科学研究費助成事業
2017年06月30日 - 2019年03月31日
清野 研一郎, バグダーディ ムハンマド, 和田 はるか
ドナー脾臓細胞をレシピエントへ輸注することでドナー特異的に免疫寛容を誘導できることが明らかとなった。さらに脾臓に含まれるB細胞分画のみの移入によってドナー特異的に皮膚移植片の長期生着が達成可能であることがわかった。一方でドナー脾臓中のT細胞の移入は移植片の長期生着に寄与しなかった。また、免疫抑制剤投与下で生着を維持した皮膚移植片からiPS細胞を樹立し、多分化能（テラトーマ形成）、未分化マーカーの発現、増殖能等に異常がないことを確認した。
日本学術振興会, 挑戦的研究(萌芽), 北海道大学, 17K19691 - 人工多能性幹細胞由来のマクロファージ様免疫抑制性細胞を用いたぶどう膜網膜炎の制御
科学研究費助成事業
2016年04月01日 - 2019年03月31日
南場 研一, 清野 研一郎, 北市 伸義
マウス脾臓B細胞由来の人工多能性幹（iPS）細胞から誘導したマクロファージ様免疫抑制性細胞(iPS-SCs)をヒト視細胞間レチノイド結合蛋白由来合成ペプチド（hIRBPp）1-20抗原から作製したマウス実験的自己免疫性ぶどう膜網膜炎 (EAU)に腹腔内投与することにより、眼底所見による臨床学的重症度とHE染色による組織学的重症度は、ともに対照群に比べ有意に炎症が軽症化した。In vitroの実験でもマウスEAUから採取したhIRBPp1-20抗原特異的なCD4陽性T細胞とhIRBPp1-20抗原と抗原提示細胞にiPS-SCsを加えて共培養すると、CD4陽性T細胞の増殖は有意に抑制された。
日本学術振興会, 基盤研究(C), 北海道大学, 16K11310 - ケロイドの免疫細胞治療を目指して！～制御性T細胞は炎症＆線維化を抑制する～
科学研究費助成事業
2014年04月01日 - 2017年03月31日
村尾 尚規, 舟山 恵美, 山本 有平, 小山 明彦, 七戸 龍司, 古川 洋志, 林 利彦, 齋藤 典子, 関堂 充, 清野 研一郎
ケロイドは慢性炎症性線維化疾患であり、CD4陽性T細胞などの炎症性細胞が病態に大きく寄与する。CD4陽性T細胞のサブセットの一つである制御性T細胞は炎症・免疫反応を制御し、抗線維化作用を有する。ケロイド内での炎症制御機構、線維化抑制機構について線維芽細胞ーCD4陽性T細胞共培養モデルを用いて検証した。制御性T細胞などが主に産生する炎症抑制性サイトカインIL-10は、ケロイド線維芽細胞への直接的な作用より、CD4陽性T細胞の各サブセット間の相互作用に寄与し、間接的にケロイド線維芽細胞に対して抗炎症作用、抗線維化作用を示す可能性が示された。
日本学術振興会, 基盤研究(B), 北海道大学, 26293379 - 悪性黒色腫における腫瘍免疫の破綻を解明する！～マウスリンパ浮腫モデルを用いて～
科学研究費助成事業
2013年04月01日 - 2016年03月31日
山本 有平, 古川 洋志, 小山 明彦, 林 利彦, 舟山 恵美, 村尾 尚規, 清野 研一郎, 七戸 龍司, 大芦 孝平, 齋藤 典子, 関堂 充
本研究は、我々が過去に報告したマウス後肢におけるin transit転移モデルを使用して、予後不良因子であるin transit転移の成立機構を解明することを目的とした。また、in transit転移モデルの基盤となるマウス後肢のリンパ浮腫モデルを改良し、安定的に浮腫が再現することを試みた。更にこのモデルを使用して、後肢浮腫モデルの分子生物学的解析を可能とした。リンパ管機能不全をきたした腫瘍微小環境における腫瘍免疫の破綻が、腫瘍の増殖や転移に影響を与えることが示唆された。
日本学術振興会, 基盤研究(B), 北海道大学, 25293361 - ES細胞を用いた新しい免疫制御法に関する研究
科学研究費助成事業
2006年 - 2007年
清野 研一郎
NKT細胞は自然免疫と獲得免疫をつなぐ重要な免疫制御性T細胞の一つである。免疫制御におけるNKT細胞研究の今後の発展を考えた場合、NKT細胞の操作・移入により免疫寛容状態を人為的に誘導できるかどうかが重要なポイントである。またより強固で安全な免疫制御法を確立するためにはその際の分子メカニズムを詳細に知る必要がある。我々は本研究によりNKT細胞の操作・移入による人為的な免疫制御法の確立に向けて、ES細胞など未分化細胞からの樹状細胞やNKT細胞の誘導が可能であるかどうか検討した。またその際の分子メカニズムと制御法について検討を行った。
まず、マウスES細胞を試験管内でOP9細胞とGM-CSFを用いて培養することで樹状細胞様の細胞を分化・誘導し、NKT細胞との共培養に用いた。ES細胞由来樹状細胞はCD11cやCD80/86を発現しており、α-GalCerをパルスしてからNKT細胞と共培養するとサイトカイン産生を誘導することが可能であった。この際、IL-10存在下で培養すると、NKT細胞、樹状細胞ともに炎症性サイトカイン産生の能力が低下し、逆にIL-10産生性が亢進した。NKT細胞の繰り返し刺激による樹状細胞側のIL-10の誘導は、生体内の樹状細胞で見られるよりは軽度であった。
本研究で我々はPLA2のひとつiPLA2の異常により生体内でNKT細胞の比率が高まることを見出した。iPLA2の阻害剤BELを用いて胎仔胸腺培養を行うとNKT細胞の比率が増加し、NKT細胞の分化においてiPLA2の酵素活性が重要な役割を果たしていることが示唆された。骨髄幹細胞や胎児肝臓からの試験管内T細胞誘導においてNKT細胞を分化させることは困難であったが、このiPLA2機能を制御することでNKT細胞の分化効率が変化する可能性が示された。
日本学術振興会, 基盤研究(C), 聖マリアンナ医科大学, 18590478 - 細胞培養の改善に関する技術開発
競争的資金 - 細胞分取に関する技術開発
競争的資金 - 免疫制御に関する創薬
競争的資金 - 癌の先端的治療
競争的資金 - 移植に関する諸問題
競争的資金 - 免疫実験一般
競争的資金 - 臓器移植、癌、自己免疫疾患などの難病に対する近未来的治療法の一つとして、新しい免疫療法・細胞治療法を開発するための基盤的研究を展開している。現在は、糖脂質を認識し免疫調節作用を担うことが近年明らかとなったNKT 細胞系の生物学の解明に注力しており、その免疫制御のしくみなどについて研究
競争的資金
