MHC CLASS I GENES AND AUTOIMMUNE DIABETES

MHC I 类基因与自身免疫性糖尿病

• 批准号: 2767906
• 负责人: ROBERT T GRASER
• 金额: $ 3.17万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-24 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2767906
• 关键词: MHC class I antigen; NOD mouse; T cell receptor; T lymphocyte; diabetes mellitus genetics; genetically modified animals; insulin dependent diabetes mellitus; major histocompatibility complex; pathologic process

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.

胰岛素依赖性糖尿病（insulin dependent diabetes mellitus，IDDM）是一种由主要组织相容性复合体（major histocompatibility complex，MHC）内外的多个易感基因（multiple susceptibility，Idd）控制的T细胞介导的自身免疫性疾病。 MHC II类基因的不寻常变异明显有助于糖尿病易感性。 然而，尽管事实上它们代表了在缺乏自身免疫倾向的许多菌株中也发现的常见等位基因，但NOD小鼠表达的MHC I类基因产物（例如Kd、Db）介导对IDDM起始至关重要的T细胞应答。 本项目要检验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限制性糖尿病性T细胞克隆转基因表达T细胞受体（TCR）的NOD小鼠群。 在目的1中，该TCR转基因原种将用于鉴定体内活化MHC I类限制性致糖尿病T细胞的需要。 目的2将使用TCR转基因储备物来确定是否存在任何非MHC I类限制性致糖尿病T细胞。目的2将使用TCR转基因储备物来确定是否有任何非MHC Idd基因控制致糖尿病的MHC I类限制性T细胞的选择或归巢和/或活化。 目的3将确定Kd和/或Db MHC I类变体是否单独或联合导致NOD小鼠中的IDDM。 这将通过NOD和ALR小鼠的异交分析进行测试，NOD和ALR小鼠共享所有II类，但仅共享一些MHC I类等位基因。