Inhibition of Th17 cells regulates autoimmune diabetes in NOD mice.
Inhibition of Th17 cells regulates autoimmune diabetes in NOD mice.
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DOI：
10.2337/db08-1113
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发表时间：
2009-06
期刊：
影响因子：
7.7
通讯作者：
Shapiro AM
中科院分区：
文献类型：
--
作者：
Emamaullee JA;Davis J;Merani S;Toso C;Elliott JF;Thiesen A;Shapiro AM
辅助性T细胞17（Th 17）群是分泌白细胞介素（IL）-17的CD 4阳性T细胞的一个亚群，其与自身免疫性疾病（包括多发性硬化症和狼疮）有关。靶向Th 17效应分子IL-17或直接抑制Th 17群体（IL-25）的治疗剂已在自身免疫的动物模型中显示出前景。Th 17细胞在1型糖尿病中的作用尚不清楚。本研究探讨了中和性抗IL-17和重组IL-25对自发性自身免疫性糖尿病模型NOD小鼠糖尿病发展的影响。尽管用抗IL-17或IL-25治疗对年轻（<5周）NOD小鼠的糖尿病发展没有影响，但当在10周龄开始治疗时，任一干预都预防了糖尿病（P < 0.001）。胰岛炎评分和免疫荧光染色显示抗IL-17和IL-25均显著减少胰岛周围T细胞浸润。两种治疗也降低了GAD 65自身抗体水平。胰腺淋巴结的分析显示，两种治疗均增加了调节性T细胞的频率。进一步的研究表明，在成熟糖尿病期间，IL-25治疗上级于抗IL-17，因为它在90%的治疗动物中促进了新发糖尿病的缓解期。同样，IL-25延迟同基因胰岛移植后复发性自身免疫，而抗IL-17则没有益处。GAD 65特异性ELISpot和CD 4阳性过继转移研究表明，IL-25治疗导致T细胞介导的针对自身免疫的显性保护作用。这些研究表明，Th 17细胞参与了自身免疫性糖尿病的发病机制。Th 17靶向治疗剂的进一步开发可能对这种疾病有益。
The T helper 17 (Th17) population, a subset of CD4-positive T-cells that secrete interleukin (IL)-17, has been implicated in autoimmune diseases, including multiple sclerosis and lupus. Therapeutic agents that target the Th17 effector molecule IL-17 or directly inhibit the Th17 population (IL-25) have shown promise in animal models of autoimmunity. The role of Th17 cells in type 1 diabetes has been less clear. The effect of neutralizing anti–IL-17 and recombinant IL-25 on the development of diabetes in NOD mice, a model of spontaneous autoimmune diabetes, was investigated in this study. Although treatment with either anti–IL-17 or IL-25 had no effect on diabetes development in young (<5 weeks) NOD mice, either intervention prevented diabetes when treatment was started at 10 weeks of age (P < 0.001). Insulitis scoring and immunofluorescence staining revealed that both anti–IL-17 and IL-25 significantly reduced peri-islet T-cell infiltrates. Both treatments also decreased GAD65 autoantibody levels. Analysis of pancreatic lymph nodes revealed that both treatments increased the frequency of regulatory T-cells. Further investigation demonstrated that IL-25 therapy was superior to anti–IL-17 during mature diabetes because it promoted a period of remission from new-onset diabetes in 90% of treated animals. Similarly, IL-25 delayed recurrent autoimmunity after syngeneic islet transplantation, whereas anti–IL-17 was of no benefit. GAD65-specific ELISpot and CD4-positive adoptive transfer studies showed that IL-25 treatment resulted in a T-cell–mediated dominant protective effect against autoimmunity. These studies suggest that Th17 cells are involved in the pathogenesis of autoimmune diabetes. Further development of Th17-targeted therapeutic agents may be of benefit in this disease.