Development of the prediction marker and the preemptive therapy for chronic GVHD based on abnormal B cell homeostasis during the acute phase of allogeneic HSCT
| Project/Area Number |
20K08753
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 54010:Hematology and medical oncology-related
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| Research Institution | Okayama University |
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Principal Investigator |
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | 血液内科学 / 造血幹細胞移植学 / 免疫寛容 / 制御性T細胞 / 同種造血細胞移植 / 慢性移植片対宿主病 / 移植後シクロフォスファミド / GVHD / B細胞 / 慢性GVHD / 同種造血幹細胞移植 / 移植後シクロフォスファミド法 / 移植片対宿主病 |
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| Outline of Research at the Start |
同種造血幹細胞移植後の慢性GVHDは移植サバイバーのQOLを著しく阻害する重大な合併症である。いったん重症化すると治療に抵抗することが多いが、確度の高い発症リスク評価と発症前からの先制治療は確立されていない。本研究では、①移植後急性期のB細胞恒常性モニタリングから、その後の慢性GVHD発症を予測するスコアリングシステムを構築し、②さらに、このB細胞恒常性異常を抑制できる先制的治療法を探索する。
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| Outline of Final Research Achievements |
Acute GVHD clinically develops when barrier organs such as the skin, liver, and intestinal tract are damaged above the tissue tolerance threshold by alloimmune responses with mature donor T cells. In contrast, the significance of allo-immunity to development of chronic GVHD had not been well known. In the present study, the exploratory clinical sample analyses and the validation experiments in a murine BMT model revealed that damage to primary lymphoid organs such as the bone marrow and thymus from alloimmune reactions by donor mature T cells was associated with subsequent failure of lymphogenesis of B-cell and Treg. Our results demonstrated that he functional damage of the bone marrow is the starting point of abnormal B-cell homeostasis after HSCT, and the theoretical validity of a therapeutic strategy that suppresses the onset of chronic GVHD by strategically preserving the primary lymphoid organs in acute phase.
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| Academic Significance and Societal Importance of the Research Achievements |
慢性GVHDの病態基盤としてのB細胞恒常性異常が起こるメカニズム、またこれへの治療的介入については十分な検討がなされていなかった。今回の研究成果により、移植後超急性期の同種T細胞免疫による骨髄損傷が長期的なB細胞系列および制御性T細胞の再構築不全をきたし、慢性GVHDの発症に関与していることが明らかとなった。今回の結果を基礎として、現在、B細胞新生不全および慢性GVHD発症を予測するバイオマーカーの同定へ向けて、移植急性期における骨髄微小環境の網羅的な細胞遺伝子学的解析を進めている。一連の基礎・臨床研究は、客観的バイオマーカーに基づく慢性GVHDの評価と治療法の確立への基盤となる。
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Report
(4 results)
Research Products
(5 results)
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[Journal Article] Hematopoietic stem cell-derived Tregs are essential for maintaining favorable B cell lymphopoiesis following posttransplant cyclophosphamide2023
Author(s)
Sumii Y, Kondo T, Ikegawa S, Fukumi T, Iwamoto M, Nishimura MF, Sugiura H, Sando Y, Nakamura M, Meguri Y, Matsushita T, Tanimine N, Kimura M, Asada N, Ennishi D, Maeda Y, Matsuoka KI.
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Journal Title
JCI Insight
Volume: 8
Issue: 8
Pages: 1-21
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Post-transplantation cyclophosphamide restores early B-cell lymphogenesis that suppresses subsequent chronic graft-versus-host disease2021
Author(s)
Iwamoto M, Ikegawa S, Kondo T, Meguri Y, Nakamura M, Sando Y, Sugiura H, Sumii Y, Asada N, Ennishi D, Nishimori H, Fujii K, Fujii N, Shibakura M, Maeda Y, Matsuoka KI.
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Journal Title
Bone Marrow Transplant
Volume: 56
Issue: 4
Pages: 956-959
DOI
Related Report
Peer Reviewed
