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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 11.1 ) 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 细胞免疫的药理学调节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是功能齐全的调节性 T 细胞缺陷。DNA 甲基化抑制剂先前已被证明可促进调节性 T 细胞反应,在本研究中,我们评估了它们改善慢性和急性类风湿性关节炎动物模型的潜力。在测试的药物中,地西他滨是最有效的,产生持续的治疗效果,该效果依赖于吲哚胺 2,3-双加氧酶 (IDO),并与诱导调节性 T 细胞的扩增有关,尤其是在疾病活动部位。地西他滨治疗还以高度选择性的方式引起活动性关节炎中 Th1 和 Th17 细胞的凋亡。这种选择性的分子基础被证明是 ENT1,一种核苷转运蛋白,这有助于药物进入细胞内,并在活动性关节炎期间对效应 T 细胞进行上调。进一步表明,地西他滨的短期治疗会导致产生能够在过继转移后抑制关节炎的调节性 T 细胞群。总之,描述了一种使用已批准药物的治疗方法,该方法可有效治疗活动性炎症性疾病并产生具有 IDO 依赖性维持缓解能力的强大调节性 T 细胞。

更新日期:2021-05-03
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