2023 Fiscal Year Final Research Report
Identification of the splenic plasma cells niche that regulate inhibitor production in mice with hemophilia A
Project/Area Number |
21K07825
|
Research Category |
Grant-in-Aid for Scientific Research (C)
|
Allocation Type | Multi-year Fund |
Section | 一般 |
Review Section |
Basic Section 52050:Embryonic medicine and pediatrics-related
|
Research Institution | Nara Medical University |
Principal Investigator |
Oda Akihisa 奈良県立医科大学, 医学部, 特任助教 (80547703)
|
Co-Investigator(Kenkyū-buntansha) |
野上 恵嗣 奈良県立医科大学, 医学部, 教授 (50326328)
北畠 正大 奈良県立医科大学, 医学部, 講師 (60457588)
|
Project Period (FY) |
2021-04-01 – 2024-03-31
|
Keywords | 脾臓 / 微小環境 / 血友病A / 抗FVIII中和抗体 / インヒビター |
Outline of Final Research Achievements |
Hemophilia A (HA) is a hereditary bleeding disorder caused by defects in endogenous factor (F)VIII. Approximately 30% of patients with severe HA treated with FVIII develop neutralizing antibodies (inhibitors) against FVIII, which render the therapy ineffective. We observed that the enhanced inhibitor production correlates with increased FVIII specific plasma cells especially in the spleen. When splenectomized or congenitally asplenic FVIII-KO mice were treated with LPS+rFVIII, the serum inhibitor levels decreased by approximately 80%. Furthermore, the transplanted plasma cells were preferentially recruited to the spleen, where they were retained and inhibitors were produced. Interestingly, plasma cells ineracted with some splenic cell subset in red pulp of spleen. Taken together, these results suggest that spleen is a critical site for the development and enhancement of FVIII-PCs.
|
Free Research Field |
免疫学
|
Academic Significance and Societal Importance of the Research Achievements |
血友病研究はAAVベクターを用いたFVIII長期発現を可能にする遺伝子治療、またはバイスペシフィック抗体(BsAb)薬の研究が主流となり、補充療法インヒビター産生機序の研究は下火傾向にある。理由は両研究においてインヒビター克服の可能性が示されたからであるが、遺伝子治療被験者数はまだ少数であり、BsAb抗体薬は十分な止血能を有していない事から、破綻性出血時には補充療法を必要とする場合がある。即ちインヒビター問題は未解決である。本研究は一貫してインヒビター産生応答の解明に取り組む。そして抗FVIII免疫応答プロセスを制御する脾臓免疫ニッチという視点から、新規細胞療法候補を当該研究分野へ提供する。
|