表观遗传药物IOX1对自身免疫性葡萄膜炎的治疗作用及机制

Autoimmune uveitis is a critical eyesight-threatening disease; however, the current treatments are still imperfect. CD4+ T cells, as the key factor in the pathogenesis of autoimmune uveitis, shows abnormality in DNA methylation during the pathogenic process. TET protein family, which is associated with the DNA demethylation process, has recently been found to be inhibited by epigenetic small molecular IOX1, which hasn’t been studied in immune research. In our previous study, we found that IOX1 could suppress Th1 and Th17 from expressing pro-inflammatory cytokines as well as fundus inflammation on murine models that have experimental autoimmune uveitis. Thus, we propose that IOX1 can be a cure for autoimmune uveitis by manipulating CD4+ T cells via TET protein family. In this study, we will investigate the regulating effect and mechanism of IOX1 on murine CD4+ T cells, including three subtypes: Th1, Th17 and Treg, as well as two statuses: Naïve and Memory in epigentic view. Furthermore, we will apply IOX1 in experimental autoimmune uveitis or adoptive transfer uveitis to determine its systemic or local effect and mechanism. This study will provide new strategies to treat autoimmune uveitis.

自身免疫性葡萄膜炎是严重的致盲性眼病，但目前治疗方案仍存不足。CD4+ T细胞是该病关键致病细胞，在疾病过程中存在异常DNA甲基化改变。TET蛋白家族与DNA去甲基化相关，而IOX1是新近发现的可以抑制TET蛋白家族的表观遗传药物。目前仍未有IOX1在自身免疫疾病方面的研究。在前期研究中，我们发现IOX1可以抑制Th1，Th17表达促炎细胞因子，并可抑制实验性自身免疫性葡萄膜炎小鼠的眼部炎症。综上，我们提出IOX1可以通过调控CD4+ T细胞的TET蛋白家族从而治疗自身免疫性葡萄膜炎的假说。本课题将从表观遗传学角度研究IOX1对小鼠CD4+ T细胞的幼稚和记忆两种状态和Th1，Th17及Treg三种亚型的致病能力的调控作用及机制，并探索IOX1局部或全身应用对实验性自身免疫性和过继免疫葡萄膜炎小鼠模型的治疗作用及相应机制，为自身免疫性葡萄膜炎治疗方案提供新的思路。

自身免疫性葡萄膜炎是严重的致盲性眼病，但目前治疗方案仍存不足。CD4+ T细胞是该病关键致病细胞，在疾病过程中存在异常DNA甲基化改变。TET蛋白家族与DNA去甲基化相关，而IOX1是新近发现的可以抑制TET蛋白家族的表观遗传药物。目前仍未有IOX1在自身免疫疾病方面的研究。通过本项目的研究，我们发现IOX1可以抑制Th1，Th17表达促炎细胞因子，并可抑制实验性自身免疫性葡萄膜炎小鼠的眼部炎症，过继免疫葡萄炎模型同样提示，经过IOX1处理后，CD4+ T细胞的致病效果明显下降，同时动物模型中，视网膜浸润CD4+ T细胞减少，同时浸润的CD4+ T细胞所表达促炎因子IFN-γ及IL-17皆明显下降。机制实验方面，IOX1可以结合到相应的IL17A的近端启动子，并干扰TET2与相应区域的结合，从而减少CpG岛的去甲基化，降低炎症蛋白的表达。综上，本项目证明了IOX1可通过表观遗传学机制，抑制CD4+ T细胞炎症因子表达，从而抑制葡萄膜炎严重程度，具有潜在的自身免疫性疾病治疗应用价值。