基于表达MHC-肽嵌合抗原受体T细胞治疗自身免疫疾病的策略和机制研究

Autoimmune diseases are a kind of immune disorders because of persistent tissue damages which express autoantigen and attacked by autoreactive immune system, in which autoreactive T cells play a key role. Therefore, efficient elimination of autoreactive T cells is an urgent problem to solve for clinical treatment of autoimmune diseases. In this prosoal, we design a MHC-peptide chimeric antigen receptor (MP-CAR) based T cell therapeutic approach that capable to targeting the T cells hosting relevant MHC-peptide specific TCRs. Our preliminary results indicate that MP-CAR structure specifically recognizes and targets the autoantigen-specific T cell receptor (TCR). In this project, we propose to explore the targeted sacavenging effect and mechanism of autoreactive T cells in vitiligo by effector T cells expressing MP-CAR, both in vitro (killing assay) and in vivo (vitiligo humanized mice). Accomplishment of the project will provide novel theoretical basis for the targeted therapy of MP-CAR in vitiligo. Furthermore, to modify and spread the MP-CAR structure is to provide a new therapeutic strategy for the treatment of autoimmune diseases with identical autoantigen.

自身免疫性疾病是机体对自身抗原发生免疫反应导致自身组织损害的疾病。自身反应性T细胞是介导自身免疫反应发生的关键。因此，开发特异性清除自身反应性T细胞的治疗策略是临床亟待解决的重要问题。申请人前期工作已设计MHC-肽嵌合抗原受体(MP-CAR)结构，能靶向识别自身抗原特异性T细胞受体(TCR)。本课题在此基础上，拟通过体外杀伤功能实验及白癜风人源化小鼠模型，利用流式细胞术、活细胞工作站、双光子荧光显微镜以及分子生物学等手段，阐明MP-CAR+的效应T细胞靶向杀伤MP特异性TCR+的靶细胞的作用及机制。为MP-CAR在白癜风疾病中的靶向治疗提供理论依据，进一步优化和拓展MP-CAR将为临床治疗提供新的治疗策略，具有重要的应用价值。

自身免疫性疾病是机体对自身抗原发生免疫反应导致自身组织损伤的疾病。自身反应性T细胞是介导自身免疫反应发生的关键。因此，开发特异性清除自身反应性T细胞的治疗策略是临床亟待解决的重要问题。申请人已经完成设计MHC-肽嵌合抗原受体(MP-CAR)结构，能靶向识别自身抗原特异性T细胞受体(TCR)，体外验证效应细胞对靶细胞的杀伤。阐明MP-CAR+的效应T细胞靶向杀伤MP特异性TCR+的靶细胞的作用及机制。为MP-CAR在白癜风疾病中的靶向治疗提供理论依据，待白癜风人源化小鼠模型构建成功，可以进一步尝试在体内验证杀伤作用。有可能拓展MP-CAR为临床治疗提供新的治疗策略。