Effects of insulin-dependent diabetes resistance alleles on CD8 tolerance in NOD

描述（由申请人提供）： NOD小鼠由于T细胞对胰岛抗原的耐受性丧失而自发地发展为1型糖尿病（T1 D）。NOD小鼠的同源品系高度保护免于T1 D的发生，因为它们具有位于两条染色体上的多个抗性等位基因（ldd 3/5小鼠）或在单条染色体上的3个连锁抗性等位基因（Idd 9），不具有高亲和力、胰岛特异性CDS T细胞。为了描述CDS耐受性恢复的机制，我们将追踪幼稚胰岛特异性CDS细胞在多个或单个Idd基因座的抗性等位基因仅在特定细胞类型中表达的情况下的路径。这将提供鉴定必须表达特异性保护性Idd基因以实现CDS耐受性的细胞的测定。然后，我们将从NOD或同源小鼠获得的相关细胞群内的候选Idd基因的基因表达与保护自身免疫相关的功能后果相关联。虽然四个亚区，Idd 3，Idd5.1，Idd5.2和Idd9.3是相对较好的特点和疾病易感性的可能的分子基础是已知的，在每种情况下，Idd5.3，Idd9.2和Idd9.1需要进一步的努力，定位克隆的Idd基因。相关性：人类和小鼠中T1 D的发生已被映射到许多遗传易感性基因座，这些基因座阻止T细胞对胰岛抗原的耐受性。通过阐明恢复这种耐受性的自然发生机制（由预防疾病的Idd基因定义），我们将更好地了解疾病的病因，并确定可用于预防T1 D的干预措施的目标。

DESCRIPTION (provided by applicant): NOD mice spontaneously develop Type 1 Diabetes (T1D) due to a loss of T cell tolerance to islet antigens. Congenic strains of NOD mice that are highly protected from the occurrence of T1D, because they have multiple resistance alleles situated on two chromosomes (ldd3/5 mice) or 3 linked resistance alleles on a single chromosome (Idd9), do not harbor high-avidity, islet-specific CDS T cells. In order to delineate the mechanism by which CDS tolerance is restored, we will trace the path of naive, islet-specific CDS cells in situations where resistance alleles at multiple or single Idd loci are expressed only in particular cell types. This will provide an assay that will identify the cell(s) that must express specific protective Idd genes to achieve CDS tolerance. We will then correlate gene expression of candidate Idd genes within the relevant cell populations obtained from NOD or congenic mice with the functional consequences that relate to protection from autoimmunity. Although four of the subregions, Idd3, Idd5.1, Idd5.2 and Idd9.3 are relatively well-characterized and the likely molecular basis of disease susceptibility is known in each case, Idd5.3, Idd9.2, and Idd9.1 require further efforts to positionally clone the Idd genes. Relevance: The occurrence of T1D in humans and mice has been mapped to a number of genetic susceptibility loci that prevent T cell tolerance to islet antigens. By elucidating naturally occurring mechanisms that restore such tolerance (as defined by Idd genes that prevent disease), we will better understand the etiology of the disease and also identify targets for interventions that can be used to prevent T1D.