MHC CLASS I GENES AND AUTOIMMUNE DIABETES

胰岛素依赖型糖尿病（IDDM）是人类和NOD小鼠的一种T细胞介导的自身免疫性疾病，由主要组织相容性复合体（MHC）内外的多个易感基因（Idd）控制。MHC II类基因的异常变异显然与糖尿病易感性有关。然而，尽管它们代表了在许多缺乏自身免疫倾向的菌株中也发现的共同等位基因，NOD小鼠表达的MHC I类基因产物（例如Kd， Db）介导了IDDM起始所必需的T细胞反应。本项目要验证的总体假设是，相对常见的Kd和/或Db MHC I类基因产物异常获得自身免疫性糖尿病的假设是，从Kd限制性糖尿病T细胞克隆中转基因表达T细胞受体（TCR）的NOD小鼠。在目标1中，该TCR转基因库存将用于确定MHC I类限制性糖尿病T细胞的体内激活需求。目的2将使用TCR转基因库存来确定是否有任何非mhc I类限制性糖尿病T细胞。Aim 2将使用TCR转基因库存来确定是否有任何非MHC Idd基因控制选择，或替代归巢和/或激活致糖尿病MHC I类限制性T细胞。目的3将确定Kd和/或Db MHC I类变异是否单独或联合导致NOD小鼠的IDDM。这将通过NOD和ALR小鼠的异交分析来验证，它们共享所有II类等位基因，但只有一些MHC I类等位基因。

Insulin dependent diabetes mellitus (IDDM) in both humans and NOD mice is a T cell mediated autoimmune disease controlled by multiple susceptibility ( Idd) genes both inside and outside of the major histocompatibility complex (MHC). Unusual variants of MHC class II genes clearly contribute to diabetes susceptibility. However, despite the fact they represent common alleles also found in many strains lacking autoimmune proclivity, the MHC class I ene products expressed by NOD mice (e.g. Kd, Db) mediate T cell responses essential to the initiation of IDDM. The overall hypothesis to be tested in this project is that the relatively common Kd and/or Db MHC class I gene products aberrantly acquire autoimmune diabetogenic hypothesis is a stock of NOD mice transgenically expressing a T cell receptor (TCR) from Kd restricted diabetogenic T cell clone. in aim 1, this TCR transgenic stock will be used to identify the requirements for in vivo activation of MHC class I restricted diabetogenic T cells. Aim 2 will use the TCR transgenic stock to determine if any non-MHC class I restricted diabetogenic T cells. Aim 2 will use the TCR transgenic stock to determine if any non-MHC Idd genes control the selection, or alternatively the homing and/or activation of diabetogenic MHC class I restricted T cells. aim 3 will determine if the Kd and/or Db MHC class I variants contribute to IDDM in NOD mice independently or in combination. This will be tested through outcross analyses of NOD and ALR mice which share all class II, but only some MHC class I alleles.