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发展为1型糖尿病(T1D)。NOD小鼠的同源株对T1D的发生具有高度保护作用，因为它们在两条染色体上有多个抗性等位基因(ldd3/5小鼠)或在一条染色体上有3个连锁抗性等位基因(Idd9)，不具有高亲和力的胰岛特异性CDS T细胞。为了阐明CDS耐受性恢复的机制，我们将在多个或单个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，追踪幼稚的、胰岛特异性CDS细胞的路径。这将提供一种鉴定细胞(S)的方法，该细胞必须表达特定的保护性IDD基因才能实现对CDS的耐受。然后，我们将把从NOD或同源小鼠获得的相关细胞群体中候选Idd基因的基因表达与保护自身免疫相关的功能后果联系起来。虽然Idd3、Idd5.1、Idd5.2和Idd9.3四个亚区的特性相对较好，并且在每个病例中都知道可能的疾病易感性的分子基础，但Idd5.3、Idd9.2和Idd9.1需要进一步努力才能对Idd基因进行定位克隆。相关性：T1D在人类和小鼠中的发生已被映射到一些防止T细胞对胰岛抗原耐受的遗传易感基因。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T1D的干预目标。

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.