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

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.

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。

类风湿关节炎(RA)严重影响患者生命和生活质量，并缺乏治愈的药物。调节性T细胞(Treg)具有治疗自身免疫性疾病的应用前景。阻碍其应用效果的一个问题是Treg细胞在炎症条件下不稳定。全反式维甲酸(all-trans retinoic acid, atRA)能维持Treg细胞的稳定性，而atRA是否也能维持RA患者nTreg的稳定性还未知。本项研究结果显示atRA能维持RA患者nTreg在炎症状态下其特异性转录因子FOXP3的表达，抑制其向Th1和Th17细胞转化。atRA能维持RA患者nTreg细胞在体内外的抑制功能。在具体分子机制上，我们发现atRA能抑制nTreg细胞表面IL-6受体CD126的表达，抑制STAT3的激活，降低RORγ的表达，从而维持Treg的稳定性。同时atRA还能促进nTreg细胞表达抑炎因子IL-10，从而促进nTreg细胞的抑制功能。研究结果对于开发调节性T细胞用于治疗类风湿关节炎具有非常重要的指导意义。