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Pharmacological modulation of T cell immunity results in long-term remission of autoimmune arthritis [Immunology and Inflammation]
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.412 ) Pub Date : 2021-05-11 , DOI: 10.1073/pnas.2100939118
Yi-Shu Huang, Wen-Yi Tseng, Felix I. L. Clanchy, Louise M. Topping, Joy Ogbechi, Kay McNamee, Dany Perocheau, Nien-Yi Chiang, Peter Ericsson, Anette Sundstedt, Zhong-Tian Xue, Leif G. Salford, Hans-Olov Sjögren, Trevor W. Stone, Hsi-Hsien Lin, Shue-Fen Luo, Richard O. Williams

Chronic inflammatory diseases like rheumatoid arthritis are characterized by a deficit in fully functional regulatory T cells. DNA-methylation inhibitors have previously been shown to promote regulatory T cell responses and, in the present study, we evaluated their potential to ameliorate chronic and acute animal models of rheumatoid arthritis. Of the drugs tested, decitabine was the most effective, producing a sustained therapeutic effect that was dependent on indoleamine 2,3-dioxygenase (IDO) and was associated with expansion of induced regulatory T cells, particularly at the site of disease activity. Treatment with decitabine also caused apoptosis of Th1 and Th17 cells in active arthritis in a highly selective manner. The molecular basis for this selectivity was shown to be ENT1, a nucleoside transporter, which facilitates intracellular entry of the drug and is up-regulated on effector T cells during active arthritis. It was further shown that short-term treatment with decitabine resulted in the generation of a population of regulatory T cells that were able to suppress arthritis upon adoptive transfer. In summary, a therapeutic approach using an approved drug is described that treats active inflammatory disease effectively and generates robust regulatory T cells with the IDO-dependent capacity to maintain remission.



中文翻译:

T细胞免疫的药理调节可导致自身免疫性关节炎的长期缓解[免疫学和炎症]

类风湿性关节炎等慢性炎症性疾病的特征在于功能完整的调节性T细胞不足。DNA甲基化抑制剂以前已显示出可促进调节性T细胞应答,在本研究中,我们评估了它们改善类风湿关节炎慢性和急性动物模型的潜力。在所测试的药物中,地西他滨是最有效的药物,其产生的持续治疗效果取决于吲哚胺2,3-二加氧酶(IDO),并且与诱导的调节性T细胞的扩增有关,尤其是在疾病活动部位。地西他滨的治疗还以高度选择性的方式引起了活动性关节炎中Th1和Th17细胞的凋亡。证明这种选择性的分子基础是ENT1,一种核苷转运蛋白,在活动性关节炎期间,它促进药物进入细胞内,并在效应T细胞上调。进一步表明,用地西他滨进行的短期治疗导致产生了能够在过继转移时抑制关节炎的调节性T细胞群。总之,描述了使用批准的药物的治疗方法,该方法有效地治疗活动性炎性疾病并产生具有IDO依赖性维持缓解能力的健壮的调节性T细胞。

更新日期:2021-05-03
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