HLA DQ TRANSGENIC MICE AS MODEL FOR DIABETES

胰岛素依赖型糖尿病的易感性和抵抗 胰岛素依赖型糖尿病（IDDM）与MHC II类基因的特定等位基因连锁。然而，在这方面， 所涉具体机制尚未确定。审查 这些基因的生物学功能，我们计划产生转基因 非肥胖糖尿病（NOD）小鼠，其中内源性II类基因被 被人类DQ基因取代 含有DQ 8等位基因DQA 1 *0301/DQB*0302的转基因，其赋予DQ 8等位基因DQA 1 *0301/DQB*0302。 人类糖尿病发展的最高风险，将直接 共注射到II类缺陷小鼠的胚胎中， 然后在致糖尿病NOD背景下饲养动物。使用 类似的策略，我们将产生表达DQ 6的转基因小鼠， 分子DQA 1 *0102、DQB*0602，其已知赋予显性保护 在人类身上。这些转基因NOD小鼠将作为体内模型系统 用于定义HLA-DQ等位基因在疾病发病机制中的功能 IDDM，并将是重要的其他组成部分，这一计划项目， 即合成DQ 8阻滞剂的测试（项目1）和 DQ 8 T细胞表位鉴定（项目3）。 该方案的具体目标是：1）产生NOD转基因小鼠 对于赋予对IDDM的易感性或抗性的人MHC基因; 2） 表征这些转基因系中的HLA-DQ表达和功能; 3） 评估HLA-DQ中胰岛细胞特异性自身免疫的发展 转基因NOD小鼠和非肽调节这一过程 HLA-DQ阻断剂; 4）检测早期T细胞对胰岛细胞的反应 DQ转基因小鼠中的抗原。

Susceptibility and resistance to insulin dependent diabetes mellitus (IDDM) are linked to particular alleles of MHC class II genes. However, the specific mechanism(s) involved have not been defined. To examine the biological functions of these genes we plan to generate transgenic nonobese diabetic (NOD) mice in which the endogenous class II genes are replaced by human DQ genes. Transgenes containing the DQ8 alleles DQA1*0301/DQB*0302, which confer the highest risk for the development of diabetes in humans, will be directly coinjected into the embryos of class II deficient mice and the resulting animals will then be bred onto the diabetogenic NOD background. Using a similar strategy we will generate transgenic mice expressing the DQ6 molecule DQA1*0102, DQB*0602, which is known to confer dominant protection in humans. These transgenic NOD mice will serve as an in vivo model system for defining the functions of the HLA DQ alleles in the pathogenesis of IDDM, and will be important for other components of this program project, namely the testing of synthetic DQ8 blockers (project 1) and the identification of DQ8 T cell epitopes (project 3). The specific aims of this proposal are to: 1) generate NOD mice transgenic for human MHC genes that confer susceptibility or resistance to IDDM; 2) characterize HLA-DQ expression and function in these transgenic lines; 3) assess the development of islet cell specific autoimmunity in the HLA-DQ transgenic NOD mice and the modulation of this process by non-peptidic HLA-DQ blockers; 4) examine the early T cell response to islet cell antigens in DQ transgenic mice.