SPONTANEOUS LOSS OF T-CELL TOLERANCE TO GLUTAMIC-ACID DECARBOXYLASE IN MURINE INSULIN-DEPENDENT DIABETES
SPONTANEOUS LOSS OF T-CELL TOLERANCE TO GLUTAMIC-ACID DECARBOXYLASE IN MURINE INSULIN-DEPENDENT DIABETES
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DOI：
10.1038/366069a0
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发表时间：
1993-11-04
期刊：
影响因子：
64.8
通讯作者：
LEHMANN, PV
中科院分区：
文献类型：
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作者：
KAUFMAN, DL;CLARESALZLER, M;LEHMANN, PV
非肥胖糖尿病（NOD）小鼠的胰岛素依赖型糖尿病（IDDM）是由t淋巴细胞介导的产生胰岛素的胰腺β细胞的破坏引起的，并可作为人类IDDM1的模型。尽管许多自身抗体与IDDM2相关，但尚不清楚在疾病过程中β细胞抗原致病性T细胞何时以及以何种方式被激活。我们在这里报道了NOD小鼠对谷氨酸脱羧酶的t -辅助性1 （Th1）反应在胰岛素发作的同时发生。这种反应最初局限于谷氨酸脱羧酶的有限区域，但后来在分子内扩散到其他决定因子。随后，t细胞对其他β细胞抗原产生反应，与反应的分子间多样化一致。通过耐受性谷氨酸脱羧酶反应性T细胞来预防自发的抗谷氨酸脱羧酶反应，阻断T细胞自身免疫对其他β细胞抗原的发展，以及胰岛素和糖尿病。我们的数据表明：(1)谷氨酸脱羧酶是诱导小鼠IDDM的关键靶抗原；(2)对谷氨酸脱羧酶的自身免疫触发t细胞对其他β细胞抗原的反应，(3)自发自身免疫性疾病可以通过对初始靶抗原的耐受性来预防。
INSULIN-DEPENDENT diabetes mellitus (IDDM) in non-obese diabetic (NOD) mice results from the T-lymphocyte-mediated destruction of the insulin-producing pancreatic beta-cells and serves as a model for human IDDM1. Whereas a number of autoantibodies are associated with IDDM2, it is unclear when and to what beta-cell antigens pathogenic T cells become activated during the disease process. We report here that a T-helper-1 (Th1) response to glutamate decarboxylase develops in NOD mice at the same time as the onset of insulitis. This response is initially limited to a confined region of glutamate decarboxylase, but later spreads intramolecularly to additional determinants. Subsequently, T-cell reactivity arises to other beta-cell antigens, consistent with intermolecular diversification of the response. Prevention of the spontaneous anti-glutamate decarboxylase response, by tolerization of glutamate decarboxylase-reactive T cells, blocks the development of T-cell autoimmunity to other beta-cell antigens, as well as insulitis and diabetes. Our data suggest that (1) glutamate decarboxylase is a key target antigen in the induction of murine IDDM; (2) autoimmunity to glutamate decarboxylase triggers T-cell responses to other beta-cell antigens, and (3) spontaneous autoimmune disease can be prevented by tolerization to the initiating target antigen.