Widespread expression of an autoantigen-GAD65 transgene does not tolerize non-obese diabetic mice and can exacerbate disease
Widespread expression of an autoantigen-GAD65 transgene does not tolerize non-obese diabetic mice and can exacerbate disease
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DOI：
10.1073/pnas.95.17.10055
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发表时间：
1998-08-18
影响因子：
11.1
通讯作者：
Hayday, AC
中科院分区：
文献类型：
--
作者：
Geng, LP;Solimena, M;Hayday, AC
谷氨酸脱羧酶（GAD）65是一种胰腺β细胞自身抗原，涉及作为T细胞的靶标，T细胞在人类和非肥胖糖尿病（NOD）小鼠中引发和维持胰岛素依赖性糖尿病（IDDM）。为了在NOD小鼠中建立对GAD 65的免疫耐受性，从而测试GAD在IDDM中的重要性，我们产生了由主要组织相容性复合物I类启动子驱动的鼠GAD 65转基因的三个品系。然而，尽管在新生和成年小鼠中广泛的转基因表达，T细胞耐受性并没有被诱导，胰岛的单核细胞浸润（胰岛炎）和糖尿病在转基因小鼠中至少与非转基因NOD小鼠一样糟糕，并且在GAD 65表达水平最高的小鼠中，疾病加重。相反，相同的转基因导入小鼠品系FvB，既不诱导胰岛炎也不诱导糖尿病，并且T细胞对GAD耐受。因此，NOD小鼠对GAD 65的耐受性的失败至少反映了中枢耐受性的基本缺陷，这在不容易患IDDM的动物中没有观察到。因此，在实验上不可能在糖尿病前期个体中诱导对GAD 65的完全耐受。此外，GAD 65转基因NOD小鼠中的自身免疫浸润仍然主要限于胰腺的事实表明，除了指导自身抗原表达的因素外，自身免疫疾病的器官特异性还受组织特异性因素的支配。
Glutamic acid decarboxylase (GAD)65 is a pancreatic beta cell autoantigen implicated as a target of T cells that initiate and sustain insulin-dependent diabetes mellitus (IDDM) in humans and in non-obese diabetic (NOD) mice. In an attempt to establish immunological tolerance toward GAD65 in NOD mice, and thereby to test the importance of GAD in IDDM, we generated three lines transgenic for murine GAD65 driven by a major histocompatibility complex class I promoter. However, despite widespread transgene expression in both newborn and adult mice, T cell tolerance was not induced, Mononuclear cell infiltration of the islets (insulitis) and diabetes were at least as bad in transgenic mice as in nontransgenic NOD mice, and in mice with the highest level of GAD65 expression, disease was exacerbated. In contrast, the same transgene introduced into mouse strain, FvB, induced neither insulitis nor diabetes, and T cells were tolerant to GAD, Thus, the failure of NOD mice to develop tolerance toward GAD65 reflects at minimum a basic defect in central tolerance, not seen in animals not predisposed to IDDM, Hence, it may not be possible experimentally to induce full tolerance toward GAD65 in prediabetic individuals. Additionally, the fact that autoimmune infiltration in GAD65 transgenic NOD mice remained largely restricted to the pancreas, indicates that the organ-specificity of autoimmune disease is dictated by tissue-specific factors in addition to those directing autoantigen expression.