Updated on 2025/03/01

写真a

 
TAKAHASHI Shuichiro
 
Organization
Hospital Clinical Departments Internal Medicine [Blood]
Other name(s)
Shu
External link

Degree

  • Doctor of Philosophy ( 2018.3   Hokkaido University )

Research Interests

  • Hematology

  • Immunotherapy

  • Hematopoietic stem cell transplantation

  • Multiple myeloma

Research Areas

  • Life Science / Hematology and medical oncology

Education

  • Hokkaido University   Graduate School of Medicine   Division of Medicine

    2014.4 - 2018.3

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    Country: Japan

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  • Yamagata University   Faculty of Medicine   School of Medicine

    2004.4 - 2010.3

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    Country: Japan

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Research History

  • Asahikawa Medical College   Division of Hematology, Department of Internal Medicine   Senior Lecturer

    2024.4

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  • Fred Hutchinson Cancer Center   Hill lab   Postdoctoral Research Fellow

    2020.9 - 2024.3

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  • 社会医療法人北楡会 札幌北楡病院   血液内科   医員

    2020.4 - 2020.8

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  • 北海道大学病院   検査・輸血部   助教

    2018.5 - 2020.3

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  • 北海道大学病院   血液内科   医員

    2018.4 - 2018.5

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  • 山形県立中央病院   内科(血液)   後期研修医

    2012.4 - 2014.3

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  • 山形県立中央病院   初期研修医

    2010.4 - 2012.3

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Professional Memberships

Papers

  • TIM-3+ CD8 T cells with a terminally exhausted phenotype retain functional capacity in hematological malignancies. Reviewed International journal

    Simone A Minnie, Olivia G Waltner, Ping Zhang, Shuichiro Takahashi, Nicole S Nemychenkov, Kathleen S Ensbey, Christine R Schmidt, Samuel R W Legg, Melissa Comstock, Julie R Boiko, Ethan Nelson, Shruti S Bhise, Alec B Wilkens, Motoko Koyama, Madhav V Dhodapkar, Marta Chesi, Stanley R Riddell, Damian J Green, Andrew Spencer, Scott N Furlan, Geoffrey R Hill

    Science immunology   9 ( 94 )   eadg1094   2024.4

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    Chronic antigen stimulation is thought to generate dysfunctional CD8 T cells. Here, we identify a CD8 T cell subset in the bone marrow tumor microenvironment that, despite an apparent terminally exhausted phenotype (TPHEX), expressed granzymes, perforin, and IFN-γ. Concurrent gene expression and DNA accessibility revealed that genes encoding these functional proteins correlated with BATF expression and motif accessibility. IFN-γ+ TPHEX effectively killed myeloma with comparable efficacy to transitory effectors, and disease progression correlated with numerical deficits in IFN-γ+ TPHEX. We also observed IFN-γ+ TPHEX within CD19-targeted chimeric antigen receptor T cells, which killed CD19+ leukemia cells. An IFN-γ+ TPHEX gene signature was recapitulated in TEX cells from human cancers, including myeloma and lymphoma. Here, we characterize a TEX subset in hematological malignancies that paradoxically retains function and is distinct from dysfunctional TEX found in chronic viral infections. Thus, IFN-γ+ TPHEX represent a potential target for immunotherapy of blood cancers.

    DOI: 10.1126/sciimmunol.adg1094

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  • Regulatory T cells suppress myeloma-specific immunity during autologous stem cell mobilization and transplantation. Reviewed International journal

    Shuichiro Takahashi, Simone A Minnie, Kathleen S Ensbey, Christine R Schmidt, Tomoko Sekiguchi, Samuel R W Legg, Ping Zhang, Motoko Koyama, Stuart D Olver, Alika D Collinge, Sara Keshmiri, Melissa L Comstock, Antiopi Varelias, Damian J Green, Geoffrey R Hill

    Blood   143 ( 16 )   1656 - 1669   2024.4

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)  

    Autologous stem cell transplantation (ASCT) is the standard of care consolidation therapy for eligible patients with myeloma but most patients eventually progress, an event associated with features of immune escape. Novel approaches to enhance antimyeloma immunity after ASCT represent a major unmet need. Here, we demonstrate that patient-mobilized stem cell grafts contain high numbers of effector CD8 T cells and immunosuppressive regulatory T cells (Tregs). We showed that bone marrow (BM)-residing T cells are efficiently mobilized during stem cell mobilization (SCM) and hypothesized that mobilized and highly suppressive BM-derived Tregs might limit antimyeloma immunity during SCM. Thus, we performed ASCT in a preclinical myeloma model with or without stringent Treg depletion during SCM. Treg depletion generated SCM grafts containing polyfunctional CD8 T effector memory cells, which dramatically enhanced myeloma control after ASCT. Thus, we explored clinically tractable translational approaches to mimic this scenario. Antibody-based approaches resulted in only partial Treg depletion and were inadequate to recapitulate this effect. In contrast, a synthetic interleukin-2 (IL-2)/IL-15 mimetic that stimulates the IL-2 receptor on CD8 T cells without binding to the high-affinity IL-2Ra used by Tregs efficiently expanded polyfunctional CD8 T cells in mobilized grafts and protected recipients from myeloma progression after ASCT. We confirmed that Treg depletion during stem cell mobilization can mitigate constraints on tumor immunity and result in profound myeloma control after ASCT. Direct and selective cytokine signaling of CD8 T cells can recapitulate this effect and represent a clinically testable strategy to improve responses after ASCT.

    DOI: 10.1182/blood.2023022000

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  • TIGIT inhibition and lenalidomide synergistically promote antimyeloma immune responses after stem cell transplantation in mice. Reviewed International journal

    Simone A Minnie, Olivia G Waltner, Kathleen S Ensbey, Stuart D Olver, Alika D Collinge, David P Sester, Christine R Schmidt, Samuel Rw Legg, Shuichiro Takahashi, Nicole S Nemychenkov, Tomoko Sekiguchi, Gregory Driessens, Ping Zhang, Motoko Koyama, Andrew Spencer, Leona A Holmberg, Scott N Furlan, Antiopi Varelias, Geoffrey R Hill

    The Journal of clinical investigation   133 ( 4 )   2023.2

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    Autologous stem cell transplantation (ASCT) with subsequent lenalidomide maintenance is standard consolidation therapy for multiple myeloma, and a subset of patients achieve durable progression-free survival that is suggestive of long-term immune control. Nonetheless, most patients ultimately relapse, suggesting immune escape. TIGIT appears to be a potent inhibitor of myeloma-specific immunity and represents a promising new checkpoint target. Here we demonstrate high expression of TIGIT on activated CD8+ T cells in mobilized peripheral blood stem cell grafts from patients with myeloma. To guide clinical application of TIGIT inhibition, we evaluated identical anti-TIGIT antibodies that do or do not engage FcγR and demonstrated that anti-TIGIT activity is dependent on FcγR binding. We subsequently used CRBN mice to investigate the efficacy of anti-TIGIT in combination with lenalidomide maintenance after transplantation. Notably, the combination of anti-TIGIT with lenalidomide provided synergistic, CD8+ T cell-dependent, antimyeloma efficacy. Analysis of bone marrow (BM) CD8+ T cells demonstrated that combination therapy suppressed T cell exhaustion, enhanced effector function, and expanded central memory subsets. Importantly, these immune phenotypes were specific to the BM tumor microenvironment. Collectively, these data provide a logical rationale for combining TIGIT inhibition with immunomodulatory drugs to prevent myeloma progression after ASCT.

    DOI: 10.1172/JCI157907

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  • Ruxolitinib protects skin stem cells and maintains skin homeostasis in murine graft-versus-host disease Reviewed

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

    Blood   131 ( 18 )   2074 - 2085   2018.5

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:American Society of Hematology  

    <title>Key Points</title>
    Skin GVHD targets Lgr5+ HFSCs in association with impaired hair regeneration and wound healing. Topical ruxolitinib, unlike corticosteroids, protects Lgr5+ skin stem cells and maintains skin homeostasis in skin GVHD.

    DOI: 10.1182/blood-2017-06-792614

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  • Microbiota dictate T cell clonal selection to augment graft-versus-host disease after stem cell transplantation. Reviewed International journal

    Albert C Yeh, Motoko Koyama, Olivia G Waltner, Simone A Minnie, Julie R Boiko, Tamer B Shabaneh, Shuichiro Takahashi, Ping Zhang, Kathleen S Ensbey, Christine R Schmidt, Samuel R W Legg, Tomoko Sekiguchi, Ethan Nelson, Shruti S Bhise, Andrew R Stevens, Tracy Goodpaster, Saranya Chakka, Scott N Furlan, Kate A Markey, Marie E Bleakley, Charles O Elson, Philip H Bradley, Geoffrey R Hill

    Immunity   57 ( 7 )   1648 - 1664   2024.7

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    Allogeneic T cell expansion is the primary determinant of graft-versus-host disease (GVHD), and current dogma dictates that this is driven by histocompatibility antigen disparities between donor and recipient. This paradigm represents a closed genetic system within which donor T cells interact with peptide-major histocompatibility complexes (MHCs), though clonal interrogation remains challenging due to the sparseness of the T cell repertoire. We developed a Bayesian model using donor and recipient T cell receptor (TCR) frequencies in murine stem cell transplant systems to define limited common expansion of T cell clones across genetically identical donor-recipient pairs. A subset of donor CD4+ T cell clonotypes differentially expanded in identical recipients and were microbiota dependent. Microbiota-specific T cells augmented GVHD lethality and could target microbial antigens presented by gastrointestinal epithelium during an alloreactive response. The microbiota serves as a source of cognate antigens that contribute to clonotypic T cell expansion and the induction of GVHD independent of donor-recipient genetics.

    DOI: 10.1016/j.immuni.2024.05.018

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

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

    Blood   2024.6

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

    DOI: 10.1182/blood.2023023060

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  • Calcineurin inhibition rescues alloantigen-specific central memory T cell subsets that promote chronic GVHD. Reviewed International journal

    Yewei Wang, Md Ashik Ullah, Olivia G Waltner, Shruti S Bhise, Kathleen S Ensbey, Christine R Schmidt, Samuel Rw Legg, Tomoko Sekiguchi, Ethan L Nelson, Rachel D Kuns, Nicole S Nemychenkov, Erden Atilla, Albert C Yeh, Shuichiro Takahashi, Julie R Boiko, Antiopi Varelias, Bruce R Blazar, Motoko Koyama, Simone A Minnie, Andrew D Clouston, Scott N Furlan, Ping Zhang, Geoffrey R Hill

    The Journal of clinical investigation   134 ( 11 )   2024.6

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    Calcineurin inhibitors (CNIs) constitute the backbone of modern acute graft-versus-host disease (aGVHD) prophylaxis regimens but have limited efficacy in the prevention and treatment of chronic GVHD (cGVHD). We investigated the effect of CNIs on immune tolerance after stem cell transplantation with discovery-based single-cell gene expression and T cell receptor (TCR) assays of clonal immunity in tandem with traditional protein-based approaches and preclinical modeling. While cyclosporin and tacrolimus suppressed the clonal expansion of CD8+ T cells during GVHD, alloreactive CD4+ T cell clusters were preferentially expanded. Moreover, CNIs mediated reversible dose-dependent suppression of T cell activation and all stages of donor T cell exhaustion. Critically, CNIs promoted the expansion of both polyclonal and TCR-specific alloreactive central memory CD4+ T cells (TCM) with high self-renewal capacity that mediated cGVHD following drug withdrawal. In contrast to posttransplant cyclophosphamide (PT-Cy), CSA was ineffective in eliminating IL-17A-secreting alloreactive T cell clones that play an important role in the pathogenesis of cGVHD. Collectively, we have shown that, although CNIs attenuate aGVHD, they paradoxically rescue alloantigen-specific TCM, especially within the CD4+ compartment in lymphoid and GVHD target tissues, thus predisposing patients to cGVHD. These data provide further evidence to caution against CNI-based immune suppression without concurrent approaches that eliminate alloreactive T cell clones.

    DOI: 10.1172/JCI170125

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  • R-Spondin1 protects gastric stem cells and mitigates gastric GVHD in allogeneic hematopoietic stem cell transplantation. Reviewed International journal

    Eiko Hayase, Takahide Ara, Yumika Saito, Shuichiro Takahashi, Kosuke Yoshioka, Hiroyuki Ohigashi, Reiki Ogasawara, Emi Yokoyama, Tomohiro Yamakawa, Ko Ebata, Yuta Hasegawa, Kazuma Tomizuka, Takanori Teshima

    Blood advances   8 ( 3 )   725 - 731   2024.2

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    Graft-versus-host disease (GVHD) is the major obstacle to performing allogeneic hematopoietic cell transplantation (allo-HCT). We and others have shown that intestinal stem cells are targeted in lower gastrointestinal GVHD. A leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5)-expressing gastric stem cells (GSCs) reside at the base of the gastric glands in mice. After experimental allo-HCT, Lgr5+ GSCs significantly decreased. Parietal cells, which underwent continuous renewal by GSCs, were injured in gastric GVHD, leading to failure of gastric acidification and aerobic bacterial overgrowth in the duodenum. Fate-mapping analysis demonstrated that administration of R-Spondin1 (R-Spo1) that binds to Lgr5 for 6 days in naïve mice significantly increased proliferating epithelial cells derived from Lgr5+ GSCs. R-Spo1 administered on days -3 to -1 and from days +1 to +3 of allo-HCT protected GSCs, leading to amelioration of gastric GVHD and restoration of gastric acidification, and suppression of aerobic bacterial overgrowth in the duodenum. In conclusion, Lgr5+ GSCs were targeted by gastric GVHD, resulting in disruption of the gastric homeostasis, whereas R-Spo1 protected Lgr5+ GSCs from GVHD and maintained homeostasis in the stomach.

    DOI: 10.1182/bloodadvances.2023011034

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  • Correction to: Refined ultrasonographic criteria for sinusoidal obstruction syndrome after hematopoietic stem cell transplantation.

    Mutsumi Nishida, Junichi Sugita, Shuichiro Takahashi, Takahito Iwai, Megumi Sato, Yusuke Kudo, Satomi Omotehara, Tatsunori Horie, Ryosuke Sakano, Hitoshi Shibuya, Isao Yokota, Akihiro Iguchi, Takanori Teshima

    International journal of hematology   117 ( 3 )   468 - 468   2023.3

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  • Lithium attenuates graft-versus-host disease via effects on the intestinal stem cell niche. Reviewed International journal

    Motoko Koyama, Luke Samson, Kathleen S Ensbey, Shuichiro Takahashi, Andrew D Clouston, Paul J Martin, Geoffrey R Hill

    Blood   141 ( 3 )   315 - 319   2023.1

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    DOI: 10.1182/blood.2022015808

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  • Reactive granulopoiesis depends on T-cell production of IL-17A and neutropenia-associated alteration of gut microbiota. Reviewed International journal

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

    Proceedings of the National Academy of Sciences of the United States of America   119 ( 48 )   e2211230119   2022.11

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

    DOI: 10.1073/pnas.2211230119

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  • Peri-transplant glucocorticoids redistribute donor T-cells to the bone marrow and prevent relapse after haploidentical SCT. Reviewed International journal

    Takayuki Inoue, Motoko Koyama, Katsuji Kaida, Kazuhiro Ikegame, Kathleen S Ensbey, Luke Samson, Shuichiro Takahashi, Ping Zhang, Simone A Minnie, Satoshi Maruyama, Shinichi Ishii, Takashi Daimon, Takahiro Fukuda, Hirohisa Nakamae, Takahide Ara, Yumiko Maruyama, Ken Ishiyama, Tatsuo Ichinohe, Yoshiko Atsuta, Bruce R Blazar, Scott N Furlan, Hiroyasu Ogawa, Geoffrey R Hill

    JCI insight   6 ( 22 )   2021.10

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    Patients with acute leukemia who are unable to achieve complete remission prior to allogeneic hematopoietic stem cell transplantation (SCT) have dismal outcomes with relapse rates well in excess of 60%. Haplo-identical SCT (haplo-SCT) may allow enhanced graft-versus-leukemia (GVL) effects by virtue of HLA class I/II donor-host disparities but typically requires intensive immune-suppression with post-transplant cyclophosphamide (PT-Cy) to prevent lethal graft-versus-host disease (GVHD). Here we demonstrate in preclinical models that glucocorticoid administration from day -1 to +5 inhibits alloantigen presentation by professional recipient antigen presenting cells in the gastrointestinal tract and prevents donor T-cell priming and subsequent expansion therein. In contrast, direct glucocorticoid signaling of donor T-cells promotes chemokine and integrin signatures permissive of preferential circulation and migration into the bone marrow, promoting donor T-cell residency. This results in significant reductions in GVHD whilst promoting potent GVL effects (relapse in recipients receiving glucocorticoids, vehicle or PT-Cy was 12%, 56% and 100% respectively). Intriguingly, patients with acute myeloid leukemia not in remission that received unmanipulated haplo-SCT and peri-transplant glucocorticoids also had an unexpectedly low relapse rate at 1 year (32%: 95% CI, 18%-47%) with high overall survival at 3 years (58%: 95% CI, 38-74%). These data highlight a potentially simple and effective approach to prevent relapse in patients with otherwise incurable leukemia that could be studied in prospective randomized trials.

    DOI: 10.1172/jci.insight.153551

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  • Refined ultrasonographic criteria for sinusoidal obstruction syndrome after hematopoietic stem cell transplantation. Reviewed

    Mutsumi Nishida, Junichi Sugita, Shuichiro Takahashi, Takahito Iwai, Megumi Sato, Yusuke Kudo, Satomi Omotehara, Tatsunori Horie, Ryosuke Sakano, Hitoshi Shibuya, Isao Yokota, Akihiro Iguchi, Takanori Teshima

    International journal of hematology   114 ( 1 )   94 - 101   2021.7

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    Hepatic sinusoidal obstruction syndrome (SOS)/veno-occlusive disease is a life-threatening complication after hematopoietic stem cell transplantation (HSCT). We previously reported the efficacy of the Hokkaido Ultrasonography (US)-based scoring system (HokUS-10) for US findings. To establish easier-to-use criteria, we retrospectively evaluated US findings from 441 patients, including 30 patients with SOS using the HokUS-10 scoring system. Using logistic regression analysis, we established the novel diagnostic criteria HokUS-6. In the presence of ascites, US diagnosis was made in the presence of two of the following 6 parameters: moderate amount of ascites, the appearance of a paraumbilical vein blood flow signal, gallbladder wall thickening, portal vein dilatation, portal vein velocity decrease, and hepatic artery resistive index increase. The AUC, sensitivity, and specificity of HokUS-6 were 0.974 (95% confidence interval 0.962-0.990), 95.2%, and 96.9%, respectively. The scores were significantly higher in patients with severe SOS than in those with non-severe SOS (p = 0.013). Furthermore, the scores before HSCT were significantly higher in patients who developed SOS than in controls (p = 0.001). The HokUS-6 is an easy and useful way to diagnose and identify the risk of SOS.

    DOI: 10.1007/s12185-021-03137-3

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  • 急性前骨髄球性白血病に対する同種造血幹細胞移植27年後に発症したドナー細胞由来未分化大細胞リンパ腫の1例

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

    日本内科学会雑誌   110 ( 1 )   92 - 98   2021.1

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

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  • Reliability of an ultrasonographical scoring system for diagnosis of sinusoidal obstruction syndrome/veno-occlusive disease in patients with hematopoietic stem cell transplantation. Reviewed

    Takahito Iwai, Mutsumi Nishida, Junichi Sugita, Yusuke Kudo, Rika Takasugi, Isao Yokota, Ryo Takagi, Hitoshi Shibuya, Shuichiro Takahashi, Takanori Teshima

    Journal of medical ultrasonics (2001)   48 ( 1 )   45 - 52   2021.1

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    PURPOSE: Sinusoidal obstruction syndrome (SOS)/hepatic veno-occlusive disease (VOD) is a fatal complication after hematopoietic stem cell transplantation. We previously reported the usefulness of an ultrasonographical (US) scoring system, the Hokkaido US-based scoring system consisting of ten parameters (HokUS-10): (1) hepatomegaly in the left lobe and (2) right lobe, (3) dilatation of the main portal vein (PV), (4) hepatofugal flow in the main PV, (5) decreased velocity of the PV, (6) dilatation of the para-umbilical vein (PUV), (7) appearance of blood flow signal in the PUV, (8) gallbladder (GB) wall thickening, (9) ascites, and (10) increased resistive index of the hepatic artery, for the diagnosis of SOS/VOD. However, the reliability of this system among operators remains elusive. Therefore, we prospectively evaluated the reliability of HokUS-10. METHODS: Twenty-four healthy volunteers and 40 patients with liver dysfunction were enrolled. Inter- and intra-operator reliabilities were analyzed using three sonographers. RESULTS: The median concordance rate of HokUS-10 among three sonographers and intra-operator in 24 volunteers was 92% (95% CI: 73-98%) and 98% (95% CI: 92-100%), respectively. In all 64 cases, in terms of the reliability between two sonographers for three representative US parameters (amount of ascites, GB wall thickening, and appearance of PUV blood flow signal), the median concordance rate was more than 98% (95% CI: 86-106%). CONCLUSION: The inter- and intra-reliabilities of HokUS-10 were excellent. Thus, US might be a reliable tool for SOS/VOD diagnosis.

    DOI: 10.1007/s10396-020-01071-1

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  • Intestinal goblet cells protect against GVHD after allogeneic stem cell transplantation via Lypd8 Reviewed

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

    Science Translational Medicine   12 ( 550 )   eaaw0720 - eaaw0720   2020.7

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    Publishing type:Research paper (scientific journal)   Publisher:American Association for the Advancement of Science (AAAS)  

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

    DOI: 10.1126/scitranslmed.aaw0720

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  • Histological and magnified endoscopic evaluation of villous atrophy in gastrointestinal graft-versus-host disease. Reviewed International journal

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

    Annals of hematology   99 ( 5 )   1121 - 1128   2020.5

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

    DOI: 10.1007/s00277-020-03966-y

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  • Short-term KRP203 and posttransplant cyclophosphamide for graft-versus-host disease prophylaxis Reviewed

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

    Bone Marrow Transplantation   55 ( 4 )   787 - 795   2020.4

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    DOI: 10.1038/s41409-019-0733-8

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  • Reduced dose of MTX for GVHD prophylaxis promotes engraftment and decreases non-relapse mortality in umbilical cord blood transplantation Reviewed

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

    Annals of Hematology   99 ( 3 )   591 - 598   2020.3

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    DOI: 10.1007/s00277-020-03937-3

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  • Loss of nivolumab binding to T cell PD-1 predicts relapse of Hodgkin lymphoma. Reviewed

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

    International journal of hematology   111 ( 3 )   475 - 479   2020.3

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

    DOI: 10.1007/s12185-019-02737-4

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  • 不規則抗体スクリーニング試薬0.8%セルスクリーンJ-Alba-を用い不規則抗体の早期検出が可能であった2症例

    増田 裕弥, 伊藤 誠, 櫻澤 貴代, 魚住 諒, 渡邊 千秋, 西田 睦, 高橋 秀一郎, 杉田 純一, 豊嶋 崇徳

    日本輸血細胞治療学会誌   66 ( 1 )   57 - 57   2020.2

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  • 新生児におけるcisAB型の血液型検査反応性と発育に伴う抗原量の変化に関する検討

    櫻澤 貴代, 高橋 秀一郎, 渡邊 千秋, 伊藤 誠, 魚住 諒, 増田 裕弥, 早坂 光司, 西田 睦, 杉田 純一, 豊嶋 崇徳

    日本輸血細胞治療学会誌   66 ( 1 )   31 - 35   2020.2

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    cisA2B3型はオモテ検査での抗A、抗Bの反応が弱く、血漿中に抗Bが認められる反応態度であるが、新生児におけるcisA2B3型の反応態度に関する報告は少ない。今回、cisA2B3型が疑われる新生児の血液型反応態度と成長に伴う血液型抗原量の変化について検討した。症例は日齢0日の新生児、ABO血液型検査はカラム凝集法にてオモテ検査のみ施行し、抗A:2+、抗B:0となった。母親が血清学的検査でcisA2B3型と疑われていたことから、児の血液型精査、母児のABO遺伝子タイピング、血液型抗原量を測定した。児の赤血球の抗B吸着解離試験よりB抗原が検出され、ABO遺伝子タイピングでは母児共にcisAB01/O01と判定された。血液型抗原量は母親と比較して児のA、B抗原量は低く、特にB抗原量が著しく低かった。1歳11ヵ月時に再検査したところ、児のB抗原量は出生時よりも増加し、血漿中から抗Bが検出された。新生児のcisAB型では通常の血液型検査では検出できないB抗原量であるため、血液型判定に際しcisAB型を疑う場合はABO遺伝子タイピングや血液型抗原量の測定が有用であることが示唆された。(著者抄録)

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  • Salvage Transplantation with Cord Blood for Graft Rejection of Peripheral Blood Stem Cells due to Donor Specific Antibody Reviewed

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

    BLOOD CELL THERAPY / The official journal of APBMT   3 ( 3 )   74 - 77   2020

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

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  • G-bandで非典型転座様式を示しDEK-NUP214 mRNA検出が核型決定に有用であったAMLの一症例

    佐藤 かおり, 小栗 聡, 市川 絢子, 藤澤 真一, 西田 睦, 高橋 秀一郎, 杉田 純一, 豊嶋 崇徳

    日本染色体遺伝子検査学会雑誌   37 ( 2 )   48 - 48   2019.9

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  • Ocular instillation of vitamin A–coupled liposomes containing HSP47 siRNA ameliorates dry eye syndrome in chronic GVHD Reviewed

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

    Blood Advances   3 ( 7 )   1003 - 1010   2019.4

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    <title>Abstract</title>Chronic graft-versus-host disease (GVHD) profoundly affects the quality of life of long-term survivors of allogeneic hematopoietic stem cell transplantation (SCT). The eyes are frequently involved, and dry eye syndrome is the most common manifestation of ocular chronic GVHD. We explored the role of heat shock protein 47 (HSP47) in ocular GVHD and developed a novel antifibrotic topical therapy using vitamin A–coupled liposomes containing HSP47 small interfering RNA (siRNA) against HSP47 (VA-lip HSP47). In a mouse model of chronic GVHD, infiltration of HSP47+ fibroblasts and massive fibrosis surrounding the lacrimal ducts were observed after allogeneic SCT, leading to impaired tear secretion. After ocular instillation, VA-lip HSP47 was distributed to the lacrimal glands, knocked down HSP47 expression in fibroblasts, reduced collagen deposition, and restored tear secretion after allogeneic SCT. Ocular instillation of VA-lip HSP47 also ameliorated established lacrimal gland fibrosis and dry eye syndrome. VA-lip HSP47 eye drops are a promising prophylactic and therapeutic option against dry eye syndrome in chronic GVHD.

    DOI: 10.1182/bloodadvances.2018028431

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  • UTILITY OF LISS AS AN AUTOANTIBODY ADSORPTION METHOD FOR DETECTION OF COEXISTING ALLOANTIBODIES IN PATIENTS WITH AUTOANTIBODIES

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

    Japanese Journal of Transfusion and Cell Therapy   65 ( 1 )   98 - 102   2019.2

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    DOI: 10.3925/jjtc.65.98

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  • A role for IL-34 in osteolytic disease of multiple myeloma Reviewed International journal

    Muhammad Baghdadi, Kozo Ishikawa, Sayaka Nakanishi, Tomoki Murata, Yui Umeyama, Takuto Kobayashi, Yosuke Kameda, Hiraku Endo, Haruka Wada, Bjarne Bogen, Satoshi Yamamoto, Keisuke Yamaguchi, Ikumi Kasahara, Hiroshi Iwasaki, Mutsumi Takahata, Makoto Ibata, Shuichiro Takahashi, Hideki Goto, Takanori Teshima, Ken-ichiro Seino

    Blood advances   3 ( 4 )   541 - 551   2019.2

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    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.

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  • 自己抗体保有患者の同種抗体検出におけるLISSを用いた自己抗体吸着法の有用性の検討

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

    日本輸血細胞治療学会誌   65 ( 1 )   98 - 102   2019.2

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

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  • Essential role of IFN-γ in T cell–associated intestinal inflammation Reviewed

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

    JCI Insight   3 ( 18 )   2018.9

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    DOI: 10.1172/jci.insight.121886

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  • 成人急性リンパ性白血病におけるIKZF1欠失およびCRLF2発現の解析(Analysis of IKZF1 deletion and CRLF2 expression in adult patients with acute lymphoblastic leukemia)

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

    臨床血液   59 ( 9 )   1648 - 1648   2018.9

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  • Intestinal Lymphatic Endothelial Cells Produce R-Spondin3. Reviewed International journal

    Reiki Ogasawara, Daigo Hashimoto, Shunsuke Kimura, Eiko Hayase, Takahide Ara, Shuichiro Takahashi, Hiroyuki Ohigashi, Kosuke Yoshioka, Takahiro Tateno, Emi Yokoyama, Ko Ebata, Takeshi Kondo, Junichi Sugita, Masahiro Onozawa, Toshihiko Iwanaga, Takanori Teshima

    Scientific reports   8 ( 1 )   10719 - 10719   2018.7

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

    DOI: 10.1038/s41598-018-29100-7

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  • Vitamin A–coupled liposomes containing siRNA against HSP47 ameliorate skin fibrosis in chronic graft-versus-host disease Reviewed International journal

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

    Blood   131 ( 13 )   1476 - 1485   2018.3

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    HSP47+ myofibroblasts are accumulated in the fibrotic lesions of chronic GVHD and promote fibrosis in a CSF-1R+ macrophage-dependent manner. Vitamin A–coupled liposomes containing HSP47 siRNA abrogate HSP47 expression in myofibroblasts and ameliorate fibrosis in chronic GVHD.

    DOI: 10.1182/blood-2017-04-779934

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  • R-Spondin1 expands Paneth cells and prevents dysbiosis induced by graft-versus-host disease Reviewed

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

    JOURNAL OF EXPERIMENTAL MEDICINE   214 ( 12 )   3507 - 3518   2017.12

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    The intestinal microbial ecosystem is actively regulated by Paneth cell-derived antimicrobial peptides such as alpha-defensins. Various disorders, including graft-versus-host disease (GVHD), disrupt Paneth cell functions, resulting in unfavorably altered intestinal microbiota (dysbiosis), which further accelerates the underlying diseases. Current strategies to restore the gut ecosystem are bacteriotherapy such as fecal microbiota transplantation and probiotics, and no physiological approach has been developed so far. In this study, we demonstrate a novel approach to restore gut microbial ecology by Wnt agonist R-Spondin1 (R-Spo1) or recombinant a-defensin in mice. R-Spo1 stimulates intestinal stem cells to differentiate to Paneth cells and enhances luminal secretion of a-defensins. Administration of R-Spo1 or recombinant a-defensin prevents GVHD-mediated dysbiosis, thus representing a novel and physiological approach at modifying the gut ecosystem to restore intestinal homeostasis and host-microbiota cross talk toward therapeutic benefits.

    DOI: 10.1084/jem.20170418

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  • Graft-versus-host disease targets ovary and causes female infertility in mice Reviewed

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

    BLOOD   129 ( 9 )   1216 - 1225   2017.3

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

    DOI: 10.1182/blood-2016-07-728337

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  • alpha-Mannan induces Th17-mediated pulmonary graft-versus-host disease in mice Reviewed

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

    BLOOD   125 ( 19 )   3014 - 3023   2015.5

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

    DOI: 10.1182/blood-2014-12-615781

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  • SOS/VOD評価における超音波検査スコアHokUS-3の検者再現性に関する検討

    岩井 孝仁, 西田 睦, 工藤 悠輔, 高杉 莉佳, 横田 勲, 高木 諒, 渋谷 斉, 高橋 秀一郎, 杉田 純一, 豊嶋 崇徳

    超音波医学   47 ( Suppl. )   S344 - S344   2020.11

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  • FUNCTIONAL COMPARISON BETWEEN Spectra Optia<sup>®</sup> MNC AND CMNC MODES FOR PERIPHERAL BLOOD STEM CELL COLLECTION

    Ito Makoto, Takahashi Syuichiro, Miyashita Naohiro, Goto Hideki, Onozawa Masahiro, Shiratori Souichi, Sugita Junichi, Hashimoto Daigo, Akizawa Koji, Sato Norihiro, Teshima Takanori, Hayase Eiko, Watanabe Chiaki, Uwatoko Takayo, Uozumi Ryo, Hayashi Yasuhiro, Hayasaka Koji, Mogi Yuko, Kahata Kaoru

    Japanese Journal of Transfusion and Cell Therapy   64 ( 6 )   742 - 751   2018

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    Language:Japanese   Publisher:The Japan Society of Transfusion Medicine and Cell Therapy  

    &lt;p&gt;&lt;b&gt;Background: &lt;/b&gt;Spectra Optia&lt;sup&gt;®&lt;/sup&gt; is an apheresis system that enables peripheral blood stem cell collection (PBSCC) to be easily conducted due to its unique automated interface management system. We retrospectively analyzed the number for CD34-positive cells in collected products and the collection efficiency for CD34-positive cells between the Spectra Optia&lt;sup&gt;®&lt;/sup&gt; MNC mode (MNC group) and CMNC mode (CMNC group) for PBSCC.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Methods: &lt;/b&gt;We retrospectively analyzed 233 cases of PBSCC (autologous PBSCC: 103 cases, allogeneic PBSCC: 130 cases), which were performed in our institution between August 2013 and February 2018.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Results: &lt;/b&gt;In autologous PBSCC, there was no significant difference in the number of CD34-positive cells in collected products or the collection efficiency for CD34-positive cells between the two groups. In allogeneic PBSCC, the number of CD34-positive cells in collected products and the collection efficiency for CD34-positive cells in the CMNC group were significantly higher than those in the MNC group. Peripheral blood platelet count and hemoglobin concentration were identified as the factors influencing the collection efficiency for CD34-positive cells.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Conclusion: &lt;/b&gt;In autologous PBSCC, the number and collection efficiency for CD34-positive cells were not significantly different between the two modes, whereas in allogeneic PBSCC, the CMNC mode was more efficient for PBSCC than the MNC mode.&lt;/p&gt;

    DOI: 10.3925/jjtc.64.742

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  • Vitamin A-Coupled Liposomes Carrying siRNA Against HSP47 Ameliorate Skin Fibrosis in Chronic Graft-Versus-Host Disease

    Tomohiro Yamakawa, Daigo Hashimoto, Eiko Hayase, Shuichiro Takahashi, Takanori Teshima

    BLOOD   128 ( 22 )   2016.12

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    Language:English   Publishing type:Research paper, summary (international conference)   Publisher:AMER SOC HEMATOLOGY  

    Web of Science

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  • Molecular mechanism of graft-versus-host disease and molecular targeted therapy

    72 ( 3 )   330 - 336   2016.3

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Presentations

  • Treg Depletion During Stem Cell Mobilization Enhances Anti-myeloma Immunity After Experimental ASCT

    Shuichiro Takahash, Simone A Minnie, Samuel RW Legg, Christine R Schmid, Kathleen S Ensbey, Damian J Green, Geoffrey R Hill

    14th JSH International Symposium 2024 in Hakodate  2024.7 

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    Event date: 2024.7

    Language:English   Presentation type:Poster presentation  

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  • Regulatory T cell depletion during stem cell mobilization enhances anti-myeloma immunity after experimental autologous stem cell transplantation

    Shuichiro Takahashi MD, PhD, Simone A Minnie, PhD, Samuel RW Legg, Christine R Schmid, Kathleen S Ensbey, Damian Green, Geoffrey R Hill

    64th ASH Annual Meeting and Exposition  2022.12 

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    Event date: 2022.12

    Language:English   Presentation type:Oral presentation (general)  

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  • LGR5+ skin stem cells are targeted in GVHD and topical ruxolitinib protects them against GVHD

    Shuichiro Takahashi, Daigo Hashimoto, Eiko Hayase, Takanori Teshima

    2016.10 

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    Event date: 2016.10

    Language:English   Presentation type:Oral presentation (general)  

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  • Topical ruxolitinib protects LGR5+ stem cells in the hair follicles and ameliorates skin graft-versus-host disease

    Shuichiro Takahashi, Daigo Hashimoto, Eiko Hayase, Takanori Teshima

    BMT Tandem Meetings 2016  2016.2 

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    Event date: 2016.2

    Language:English   Presentation type:Oral presentation (general)  

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Awards

  • Abstract Achievement Award

    2022.12   American Society of Hematology   Regulatory T cell depletion during stem cell mobilization enhances anti-myeloma immunity after experimental autologous stem cell transplantation

    Shuichiro Takahashi, Simone A Minnie, Samuel RW Legg, Christine R Schmid, Kathleen S Ensbey, Damian Green, Geoffrey R Hill

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  • Best Abstract Awards

    2016.2   The American Society for Transplantation and Cellular Therapy   Topical ruxolitinib protects LGR5+ stem cells in the hair follicles and ameliorates skin graft-versus-host disease

    Shuichiro Takahashi, Daigo Hashimoto, Eiko Hayase, Takanori Teshima

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Research Projects

  • 移植片対宿主病による肝幹細胞傷害の有無と肝組織再生に与える影響についての検討

    Grant number:19K17849  2019.4 - 2020.3

    日本学術振興会  科学研究費助成事業  若手研究

    高橋 秀一郎

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    Grant amount:\4,160,000 ( Direct Cost: \3,200,000 、 Indirect Cost:\960,000 )

    骨髄移植のマウスモデルを用いた検討により、移植片対宿主病(GVHD)の発症するallogeneicマウスにおいて移植後21日目にLgr5陽性幹細胞が門脈周囲および胆管周囲に出現することが確認された。また、T細胞のレポーターマウスを用いた移植実験により、Lgr5陽性幹細胞の出現部位はT細胞の浸潤部位近傍に局在していることが判明し、GVHDによる胆管細胞傷害によりLgr5陽性幹細胞の発現が誘導されるものと考えられた。移植後28日目ではallogeneicマウスにおいてT細胞などの炎症細胞浸潤は依然として認められたが、Lgr5陽性幹細胞は減少傾向となっていた。一方で、同時期のallogeneicマウスにおいてはサイトケラチン19陽性の胆管上皮細胞が増加し胆管新生が認められた。以上の結果から、肝臓GVHDにおいては胆管上皮の傷害が生じ、傷害部位近傍にLgr5陽性幹細胞が出現し、胆管上皮の再生に寄与しているものと考えられた。
    移植後のallogeneicマウスに、移植後14日目からWnt/βカテニンシグナル伝達系の活性化因子であるR-spondin1の投与を行ったところ、コントロール群と比較してサイトケラチン19陽性細胞が増加し、正常な管腔構造を有する小胆管も増加している所見が得られた。この結果より、R-spondin1投与によりGVHDによる胆管上皮傷害後の胆管再生が促されている可能性が考えられた。
    これらの現象の機序を検討するため、現在は肝臓オルガノイドを用いたex vivoでの検討を行っている。今後は肝臓オルガノイドと移植後マウスのT細胞の共培養の系を用いて、同種反応性T細胞により肝臓オルガノイド細胞の胆管上皮細胞への分化促進を検討する。また、その際のオルガノイド細胞を用いた遺伝子発現の解析により、同種反応性T細胞による傷害によりどのような変化が生じるかについて検討したい。

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