αIIbβ3-CAAR-T“木马”诱捕清除自身反应性B细胞治疗慢性ITP的实验研究

慢性免疫性血小板减少（cITP）的治疗方法亟待突破，cITP发病机制与寡克隆B细胞产生针对血小板特异性抗原的自身抗体(PAAbs)有关，如何精准清除自身反应性B细胞及其PAAbs是本项目拟解决的关键问题。我们已在CAR-T治疗B细胞血液肿瘤中取得显著进展，最近一种由CAR-T演变而来的嵌合自身抗体受体T细胞（CAAR-T)疗法在天疱疮免疫治疗中获成功，由此我们提出cITP的治疗新策略：构建针对PAAbs的CAAR-T，在体内发挥“木马”效应，诱捕自身反应性B细胞并实施特异性杀伤。目前我们已证实αIIbβ3是与cITP相关的主要抗原，通过PDB数据库筛选到αIIbβ3与PAAbs特异性结合表位。本项目拟将αIIbβ3抗原表位与我们现有CAR-T靶头融合，构建新的“αIIbβ3-CAAR”T细胞，通过ITP-杂交瘤小鼠模型验证“木马”策略，评估靶向干预效果，为cITP治疗开辟新途径。

The treatment of chronic immune thrombocytopenia (cITP) is in urgent need of breakthrough. The mechanism of cITP is related to the production of autoantibodies (PAAbs) against platelet-specific antigens by oligoclonal B cells. To precisely clear autoreactive B cells and PA Abs is the key problem to be solved in this project. We have made significant progress in the treatment of B-cell tumors with CAR-T. Recently, a new chimeric autoantibody receptor T cell (CAAR-T) technology has emerged and has been successful in the treatment of pemphigus. We propose a new strategy for immunotherapy of cITP: construct CAAR-T against PAAbs, which play a "trojan" effect in the body, trap autoreactive B cells and perform specific killing. At present, we have confirmed that αIIbβ3 is the main antigen associated with chronic ITP, and we have found the specific binding epitope of αIIbβ3 and PAAbs by screening in the PDB database. This project intends to fuse the αIIbβ3 epitope with our existing CAR-T target, construct a new "αIIbβ3-CAAR" T cell, verify the "Trojan" hypothesis through ITP-hybridoma mouse model, evaluate the effect of targeted intervention, and open up new ways to treat cITP .