GAD-reactive CD4+ Th1 cells induce diabetes in NOD/SCID mice
GAD-reactive CD4+ Th1 cells induce diabetes in NOD/SCID mice
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DOI：
10.1172/jci119878
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发表时间：
1998-01-01
影响因子：
15.9
通讯作者：
Sherwin, RS
中科院分区：
文献类型：
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作者：
Zekzer, D;Wong, FS;Sherwin, RS
虽然谷氨酸脱羧酶(GAD)与IDDM有关，但没有直接证据表明GAD反应的T细胞在体内会导致糖尿病，为了解决这个问题，3周龄的NOD小鼠接受了两次纯化的大鼠脑GAD注射；其中一只小鼠在3周后迅速发展为糖尿病。小鼠脾细胞对纯化的GAD表现出增殖反应，并被用来产生表达编码Vβ2和Vβ12的TCRs的CD4+T细胞系5A，5A T细胞对纯化的GAD和GAD65肽524-543表现出MHC限制性的增殖反应。抗原特异性刺激后，5A T细胞分泌干扰素γ和肿瘤坏死因子α/β，但不分泌IL-4，它们对转染大鼠GAD65的结节来源的杂交瘤细胞(表达I-A(G7))也具有细胞毒作用，但不能抑制未转染的杂交瘤细胞的增殖。将5A细胞过继转移到NOD/SCID小鼠后，所有小鼠均发生了胰腺炎，83%的小鼠出现糖尿病。我们的结论是，在幼年NOD小鼠体内注射GAD可能通过激活与GAD65肽反应的糖尿病T细胞而在某些情况下引发糖尿病。我们的数据为GAD65自身免疫在IDDM的发病机制中可能是一个关键事件提供了直接的证据。
Although glutamic acid decarboxylase (GAD) has been implicated in IDDM, there is no direct evidence showing GAD-reactive T cells are diabetogenic in vivo, To address this issue, 3-wk-old NOD mice received two injections of purified rat brain GAD; one mouse rapidly developed diabetes 3 wk later. Splenocytes from this mouse showed a proliferative response to purified GAD, and were used to generate a CD4+ T cell line, designated 5A, that expresses TCRs encoding V beta 2 and V beta 12, 5A T cells exhibit a MHC restricted proliferative response to purified GAD, as well as GAD65 peptide 524-543, After antigen-specific stimulation, 5A T cells secrete IFN gamma and TNF alpha/beta, but not IL-4, They are also cytotoxic against NOD-derived hybridoma cells (expressing I-A(g7)) that were transfected with rat GAD65, but not nontransfected hybridoma cells. Adoptive transfer of 5A cells into NOD/SCID mice produced insulitis in all mice, Diabetes occurred in 83% of the mice, We conclude that GAD injection in young NOD mice may, in some cases, provoke diabetes due to the activation of diabetogenic T cells reactive to GAD65 peptides, Our data provide direct evidence that GAD65 autoimmunity may be a critical event in the pathogenesis of IDDM.