Kennedy Institute of Rheumatology, University of Oxford, Oxford OX3 7FY, United Kingdom.
Division of Rheumatology, Allergy and Immunology, Chang Gung Memorial Hospital at Linkou, Taoyuan 33305, Taiwan.
Proc Natl Acad Sci U S A. 2021 May 11;118(19). doi: 10.1073/pnas.2100939118.
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.
慢性炎症性疾病，如类风湿关节炎，其特征是完全功能的调节性 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，我们评估了它们在改善慢性和急性类风湿关节炎动物模型中的潜力。在所测试的药物中，地西他滨最为有效，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，特别是在疾病活动部位。地西他滨治疗还以高度选择性的方式导致活动性关节炎中 Th1 和 Th17 细胞的凋亡。这种选择性的分子基础被证明是 ENT1，一种核苷转运体，它促进药物的细胞内进入，并在活动性关节炎期间在效应 T 细胞上上调。进一步表明，短期使用地西他滨治疗可产生调节性 T 细胞群体，这些细胞在过继转移时能够抑制关节炎。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 依赖性能力以维持缓解的强大调节性 T 细胞。
