KLF2调控Treg细胞迁移和归巢在allo-HSCT小鼠aGVHD中的作用及机制

Graft-versus-host disease (GVHD) proved to be the major complications of patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT), which reduced survival and quality of life after transplantation. The activation of donor T cells in secondary lymphoid organ(SLO) of recipient was the pivotal point in the process of aGVHD and Treg cells were confirmed to be favorable in this status by inducing and holding immune tolerance. We found in our pre-test that strategies to maintain transcription factor KLF2 expression in Treg cells was contributed to better clinical situation and less aGVHD relevant injuries of target organs in recipients, and increasing Treg cells number as well as reduced activation of donor T cells in SLO were observed meanwhile. We changed the KLF2 expression in Treg cells in our study to define the effects of KLF2 on migration and homing of Treg cells. Furthermore, the roles and related mechanisms of KLF2 in the process of mouse aGVHD were discussed. Above all, correlated researches in our study were expected to be a novel awareness for aGVHD prevention and treatment.

移植物抗宿主病（GVHD）是异基因造血干细胞移植（allo-HSCT）后患者的主要并发症之一，降低了移植后患者生存率和生活质量。供者T细胞在受者次级淋巴器官（SLO）中活化是急性移植物抗宿主病（aGVHD)发病的中心环节，而Treg细胞通过诱导和维持供者效应T细胞免疫耐受，在aGVHD中发挥保护性作用。本课题组的前期研究表明，维持供者Treg细胞转录因子KLF2表达可减轻移植后小鼠aGVHD程度，同时受者SLO中Treg细胞数量上调，供者效应T细胞功能下降。本课题拟通过调节供者Treg细胞KLF2表达，明确KLF2对Treg细胞迁移、归巢和分布的影响，进一步探讨KLF2调节Treg细胞迁移在allo-HSCT后小鼠aGVHD中的作用及机制。课题如期完成，有望为临床防治aGVHD提供新的认识。

移植物抗宿主病（GVHD）是异基因造血干细胞移植（allo-HSCT）患者的主要并发症之一，降低了移植后患者生存率和生活质量。供者T细胞在受者次级淋巴器官（SLO）中活化是急性移植物抗宿主病（aGVHD)发病的中心环节，而调节性T细胞（Treg）细胞通过诱导和维持供者效应T细胞免疫耐受，在aGVHD中发挥保护性作用。本课题拟通过调节Kruppel 样转录因子（KLF2）表达，明确KLF2对Treg细胞迁移、归巢和分布，以及对移植后效应T细胞功能的影响，进一步探讨KLF2调节Treg细胞迁移在allo-HSCT后小鼠aGVHD中的作用及机制。本研究已有结果如下：体外研究结果表明，他汀类药物在体外不影响T细胞及其亚群的变化，但能够诱导Treg细胞的生成、降低抗原提呈细胞（APC）的活化，同时影响T细胞表面趋化因子受体（CD62L、S1P1、CCR7）的表达发挥作用。经γ射线照射后的小鼠模型显示，他汀类药物在小鼠体内不影响T细胞及其亚群的变化，能够通过降低APC细胞的活化及影响T细胞的细胞因子（IFN-γ）分泌发挥抗炎作用。他汀类药物在GVHD模型小鼠体内通过维持T细胞的静息状态，降低APC细胞的活化，调控Treg细胞的生成和分布，以及改变T细胞表面趋化因子受体CD62L、S1P1、CCR7）的表达。本项目初步探索了他汀类药物调节KLF2表达，对效应T细胞和Treg细胞生成、活化、细胞功能和迁移及分布的影响，为防治aGVHD提供了一定的理论基础和新的策略。