Nrf激动剂调控Breg细胞分化和功能减轻慢性移植物抗宿主病的机制研究

Chronic graft-versus-host disease (cGVHD) is the most common complication and the main cause of death at late-stage of allo-HSCT. There is no effective treatment approach in clinical yet. cGVHD is an autoimmune disease characterized by chronic inflammation and tissues fibrosis. Nrf2 is a novel immunomodulatory-signaling pathway, and its activation could inhibit the inflammation and fibrosis. Our previous study showed that ROS was upregulated, whereas Nrf2 was remarkably downregulated in the cGVHD target organs. Moreover, Nrf2 agonist DMF administration could inhibit cGVHD development and increased Breg cells in spleen, indicating that DMF could alleviate cGVHD through regulating Breg cells differentiation and function. Therefore, This project will be going to confirm the inhibitory role of DMF in cGVHD by two classical mice model, and then investigate the role and mechanism of Nrf2 agonist DMF in regulating Breg cells differentiation and function. Collectively, this project may provide a theoretic and experimental basis for the clinical application of Nrf2 agonist in treatment of cGVHD.

慢性移植物抗宿主病(cGVHD)是allo-HSCT晚期最常见的并发症和主要死亡原因，临床上尚无有效的防治手段。cGVHD是一种以慢性炎症和组织器官纤维化为主要表现的自身免疫病。Nrf2是一个新型的具有免疫调节作用的信号通路，活化该信号通路能够减轻炎症反应和纤维化。我们前期预实验发现cGVHD小鼠靶器官中ROS水平升高，Nrf2水平显著下调，使用Nrf2激动剂DMF能够抑制小鼠cGVHD的发生发展，DMF干预可以显著增加脾脏中的Breg细胞的水平，提示DMF可能通过调控Breg细胞的分化和功能抑制cGVHD。因此，本项目拟利用两种典型的小鼠cGVHD模型，明确DMF减轻cGVHD的作用，并进一步探究DMF减轻cGVHD是否通过诱导Breg细胞，以及DMF调控Breg分化和功能的作用及分子机制。本研究成果将为DMF应用于allo-HSCT后cGVHD的防治奠定可靠的理论和实验基础。

慢性移植物抗宿主病(cGVHD)是allo-HSCT晚期最常见的并发症和主要死亡原因，临床上尚无有效的防治手段。cGVHD是一种以慢性炎症和组织器官纤维化为主要表现的自身免疫病。Nrf2是一个新型的具有免疫调节作用的信号通路，活化该信号通路能够减轻炎症反应和纤维化。本项目以Nrf2信号通路入手，研究使用Nrf2激动剂富马酸二甲酯（DMF）抑制小鼠cGVHD的发生发展的作用及其机制。本项目成功建立了四种小鼠cGVHD模型，在四种小鼠模型中，DMF均能够显著减轻cGVHD症状，延长小鼠生存。机制研究表明DMF能够降低滤泡辅助T细胞（Tfh）的数量，降低生发中心B细胞比例，同时抑制CD4和CD8 T细胞的活化。体外研究表明DMF可以显著抑制Tfh细胞的体外分化。本研究成果将为DMF应用于allo-HSCT后cGVHD的防治奠定可靠的理论和实验基础。