AS101 ameliorates experimental autoimmune uveitis by regulating Th1 and Th17 responses and inducing Treg cells
AS101 ameliorates experimental autoimmune uveitis by regulating Th1 and Th17 responses and inducing Treg cells
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DOI：
10.1016/j.jaut.2019.02.006
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发表时间：
2019-06-01
影响因子：
12.8
通讯作者：
Caspi, Rachel R.
中科院分区：
文献类型：
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作者：
Bing, So Jin;Shemesh, Itay;Caspi, Rachel R.
AS101是一种有机碲化合物，具有多方面的免疫调节特性，以其无毒性而著称。我们测试了AS101在实验性自身免疫性葡萄膜炎（EAU）中的治疗效果，这是一种人类自身免疫性葡萄膜炎模型。出乎意料的是，AS101处理在未处理的小鼠体内诱导Treg生成。用视网膜抗原IRBP免疫EAU的小鼠和用AS101治疗的小鼠发生了减毒性疾病，用AS101治疗的视网膜特异性T细胞在体外激活的受体也发生了减毒性疾病。在这两种情况下，眼浸润效应T细胞减少，而脾脏的调节性T细胞（Treg）增加。体外机制研究表明，AS101通过抑制各自谱系特异性转录因子和下游信号的激活，限制了视网膜特异性T细胞向Th1或Th17谱系的极化。在AS101存在的情况下，视网膜特异性T细胞在体外向Th1或Th17极化时，在幼稚受体中诱导EAU的能力受损。最后，AS101在体外独立于tgf - β促进视网膜特异性T细胞向Tregs的分化。我们得出结论，AS101通过抑制效应功能的获取和表达以及促进Treg的产生来调节自身免疫T细胞，并提示AS101可作为自身免疫性葡萄膜炎的治疗方法。
AS101 is an organotellurium compound with multifaceted immunoregulatory properties that is remarkable for its lack of toxicity. We tested the therapeutic effect of AS101 in experimental autoimmune uveitis (EAU), a model for human autoimmune uveitis. Unexpectedly, treatment with AS101 elicited Treg generation in vivo in otherwise unmanipulated mice. Mice immunized for EAU with the retinal antigen IRBP and treated with AS101 developed attenuated disease, as did AS101-treated recipients of retina-specific T cells activated in vitro. In both settings, eye-infiltrating effector T cells were decreased, whereas regulatory T (Treg) cells in the spleen were increased. Mechanistic studies in vitro revealed that AS101 restricted polarization of retina-specific T cells towards Th1 or Th17 lineage by repressing activation of their respective lineage-specific transcription factors and downstream signals. Retina-specific T cells polarized in vitro towards Th1 or Th17 in the presence of AS101 had impaired ability to induce EAU in naive recipients. Finally, AS101 promoted differentiation of retina-specific T cells to Tregs in vitro independently of TGF-beta. We conclude that AS101 modulates autoimmune T cells by inhibiting acquisition and expression of effector function and by promoting Treg generation, and suggest that AS101 could be useful as a therapeutic approach for autoimmune uveitis.