全反式维甲酸稳定类风湿关节炎病人天然调节T细胞的作用和机制研究

类风湿关节炎(RA)是以关节局部滑膜侵蚀破坏与骨破坏为特征的慢性炎症和破坏性疾病。研究已经证明调节性T细胞(Treg)和Th17细胞的平衡失衡状态是RA发生和发展的关键因素之一。我们前期研究中发现全反式维甲酸(all-trans retinoic acid, atRA)处理的天然调节性T细胞(nTreg)在炎症状态下(IL-6/IL-1β)已不再向Th17或其他Th细胞转化，并且稳定表达Foxp3，维持甚至增强免疫调控活性。在本项目中，我们计划延伸到RA患者nTreg，探讨经atRA处理的RA患者nTreg能否在炎症状态仍然保持稳定的表型和功能，且通过人源化动物模型验证atRA处理的nTreg对类风湿关节炎防治作用。本研究对于发展调节性T细胞用于治疗类风湿关节炎具有非常重要的意义。

Rheumatoid arthritis (RA) is characterized by local joint synovial inflammation and bone erosion. Inblanance between T regulatory cells (Treg) and pathogenic Th17 cells is associated with RA development and progression, implicating the Treg cell therapy has a promise to treat RA. We previously identified that nature Treg(nTreg) is unstable in the inflammation but all-trans retinoic acid (atRA) markedly stabilizes the phenotype and function of nTreg isolated from colleagen-induced arthritis (CIA) mouse in the presence of inflammation. This proposal will translate study to human and determine whether atRA similarily stabilizes the phenotype and function of nTreg isolated from patients with active RA. We will develop in vitro experiments to learn whether atRA-primed nTreg from RA patients sustain Foxp3 expression, suppressive ability, being resistant to Th1, Th17 cell conversion. We will also develop humanized animal models to validate their phenotypic and functional features in vivo. This study will have a very important significance for the development of regulatory T cells for the treatment of rheumatoid arthritis.