Induction of glutamic acid decarboxylase 65-specific Th2 cells and suppression of autoimmune diabetes at late stages of disease is epitope dependent.
Induction of glutamic acid decarboxylase 65-specific Th2 cells and suppression of autoimmune diabetes at late stages of disease is epitope dependent.
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DOI：
10.4049/jimmunol.163.3.1178
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发表时间：
1999-08
影响因子：
4.4
通讯作者：
R. Tisch;Bo Wang;D. Serreze
中科院分区：
文献类型：
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作者：
R. Tisch;Bo Wang;D. Serreze
基于肽的免疫疗法是一种选择性抑制T细胞介导的β细胞破坏并治疗胰岛素依赖型糖尿病（IDDM）的策略。在这里，我们研究了是否从β细胞自身抗原谷氨酸脱羧酶65（GAD 65）的T细胞表位的面板不同的能力，以诱导非肥胖糖尿病（NOD）小鼠的Th 2细胞功能，从而防止明显的IDDM在不同的临床前阶段的疾病发展。该组由跨越aa 217-236（p217）、247-265（p247）、290-309（p290）和524-543（p524）的GAD 65特异性肽组成。我们的研究表明，当在胰岛炎发作之前给予NOD小鼠时，所有的肽都有效地预防了胰岛炎和糖尿病。相比之下，只有p217和p290的混合物阻止了表现出广泛的β细胞自身免疫性的NOD小鼠的胰岛炎和明显的IDDM的进展。用GAD 65特异性肽免疫不能阻断IL-4表达缺陷的NOD小鼠中的IDDM发展。这些发现表明，GAD 65特异性肽免疫疗法有效地抑制了向显性IDDM的进展，需要IL-4的产生，并且依赖于靶向的表位和受体中预先存在的β细胞自身免疫的程度。
Peptide-based immunotherapy is one strategy by which to selectively suppress the T cell-mediated destruction of beta cells and treat insulin-dependent diabetes mellitus (IDDM). Here, we investigated whether a panel of T cell epitopes derived from the beta cell autoantigen glutamic acid decarboxylase 65 (GAD65) differ in their capacity to induce Th2 cell function in nonobese diabetic (NOD) mice and in turn prevent overt IDDM at different preclinical stages of disease development. The panel consists of GAD65-specific peptides spanning aa 217-236 (p217), 247-265 (p247), 290-309 (p290), and 524-543 (p524). Our studies revealed that all of the peptides effectively prevented insulitis and diabetes when administered to NOD mice before the onset of insulitis. In contrast, only a mixture of p217 and p290 prevented progression of insulitis and overt IDDM in NOD mice exhibiting extensive beta cell autoimmunity. Immunization with the GAD65-specific peptides did not block IDDM development in NOD mice deficient in IL-4 expression. These findings demonstrate that GAD65-specific peptide immunotherapy effectively suppresses progression to overt IDDM, requires the production of IL-4, and is dependent on the epitope targeted and the extent of preexisting beta cell autoimmunity in the recipient.