ANTIGEN PRESENTING CELL DEFECTS IN AUTOIMMUNE DIABETES

描述（改编自研究者摘要）：本项目提出 表征抗原呈递细胞中调节缺陷的作用， 在NOD小鼠中IDD的发展中。 初步数据表明 在NOD中介导IDD易感性的一些多基因相互作用 小鼠可限制造血衍生抗原呈递的能力 细胞（APC），如B淋巴细胞、巨噬细胞和树突细胞， 激活多种免疫调节途径。 不寻常的H2g7 MHC单倍型 已被证明明显有助于受损的免疫耐受性， NOD APC的性能 然而，APC的特定群体， 在NOD小鼠中显示这些MHC控制的免疫耐受性缺陷， 未知 有三个具体目标：1。 以确定影响 基因消除B细胞对NOD小鼠APC能力的影响， 相关的股票选择和激活致糖尿病的T细胞或使他们 非致病性。 这些研究将利用培育的Ig-mu-无效突变， 到表达各种H2基因的标准NOD和修饰的NOD原种上， 评估B细胞在介导致糖尿病T细胞活化中的作用。 除了直接评估基因敲除的影响外， 包括一系列骨髓和白细胞转移研究， 描述必须表达H2g7单倍型的APC群体， 介导糖尿病性T细胞的选择和激活将是 执行。 2. 为了确定自身免疫性胰岛素依赖型糖尿病的发病机制， 在携带损害Th 1或Th 2的基因操作的NOD小鼠中发生改变 应答 这些研究将涉及培育IL-2null，IFN null， IL-4无效等位基因到NOD上，并评估它们对NOD产生的影响。 致糖尿病T细胞 3. 为了确定T细胞减少的原因 NOD巨噬细胞产生的IL-1的共刺激活性，并确定 这通过抑制Th2应答的激活而导致IDDM， β细胞自身抗原 这些研究的重点是确定 遗传机制和可能的基因产物负责的影响， 含有Idd 10的基因组片段对NOD中巨噬细胞分化的影响 小鼠 之前的研究表明，NOD的巨噬细胞不会 在骨髓生长因子的存在下完全分化， 限制了它们合成和分泌IL-1的能力。 这种表型可以 导致巨噬细胞功能的缺陷，这可能会损害 免疫调节途径的激活，包括Th2的激活 对胰岛素依赖型糖尿病有潜在保护作用的途径。 Idd 10在 这一过程得到了以下观察结果的支持： 在携带来自C57BL/6的Idd 10区域的3号染色体同源物中。 将评估IL-1表达降低的生化基础 并确定Idd 10候选基因的潜在作用。

DESCRIPTION (Adapted from Investigator's abstract): This project proposes to characterize the role of regulatory defects in antigen presenting cells in the development of IDD in the NOD mouse. Preliminary data indicate that some of the polygenic interactions that mediate susceptibility to IDD in NOD mice may limit the ability of hematopoietically derived antigen presenting cells (APC) such as B-lymphocytes, macrophages, and dendritic cells to activate various immunoregulatory pathways. The unusual H2g7 MHC haplotype has been shown to clearly contribute to the impaired immunotolerogenic capacity of NOD APC. However, the specific population(s) of APC that manifest these MHC controlled immunotolerogenic defects in NOD mice is unknown. There are 3 specific aims: 1. To determine the effect of genetically eliminating B-cells on the ability of APC from NOD mice and related stocks to select and activate diabetogenic T-cells or render them non-pathogenic. These studies will utilize the Ig-mu-null mutation bred onto standard NOD and modified NOD stocks expressing various H2 genes to assess the role of B-cells in mediating activation of diabetogenic T-cells. In addition to assessing the effects of knockouts directly, experiments involving a series of bone marrow and leukocyte transfer studies to delineate the populations of APC that must express the H2g7 haplotype to mediate the selection and activation of diabetogenic T-cells will be performed. 2. To determine the etiopathogenesis of autoimmune IDDM is altered in NOD mice carrying genetic manipulations which impair Th1 or Th2 responses. These studies will involve breeding the IL-2null, IFNnull, and IL-4null alleles onto NOD and assessing their effects on the generation of diabetogenic T-cells. 3. To identify the basis for the diminished T-cell co-stimulatory activity of IL-1 produced by NOD macrophages and determine if this contributes to IDDM by inhibiting the activation of Th2 responses to beta cell autoantigens. These studies are focused on identifying the genetic mechanisms and possibly the gene product responsible for the effects of the genomic segment containing Idd10 on macrophage differentiation in NOD mice. Previous studies have demonstrated that macrophages from NOD do not fully differentiate in the presence of myeloid growth factors and that this limits their ability to synthesize and secrete IL-1. This phenotype could result in a deficiency in macrophage function which may impair the activation of immunoregulatory pathways including the activation of Th2 pathways that are potentially protective against IDDM. The role of Idd10 in this process is supported by the observation that this defect is corrected in chromosome 3 congenics carrying the Idd10 region derived from C57BL/6. The biochemical basis for this decreased expression of IL-1 will be assessed and the potential role of the candidate gene for Idd10 will be determined.