ANTIGEN PRESENTING CELL DEFECTS IN AUTOIMMUNE DIABETES

描述：（改编自研究者摘要）：T细胞介导 自身免疫性胰岛素依赖型糖尿病是由多种易感性（Idd） 位于MHC内外的基因。在NOD小鼠中， 多基因相互作用通过减少糖尿病T细胞的表达， 造血来源的抗原呈递细胞（APC）活化的能力 各种免疫调节功能。APC的亚群包括 B淋巴细胞、巨噬细胞和树突细胞。为了部分解决APC 亚群有助于胰岛素依赖型糖尿病，研究人员生产的NOD小鼠， 功能失活的IG mu基因导致B淋巴细胞缺陷。这些B 淋巴细胞缺陷型NOD.IG mu缺失小鼠具有IDDM抗性。他们的整体 目的是描述B淋巴细胞参与 T细胞介导的自身免疫性1DDM的发生。他们找到了一个 B淋巴细胞作为APC亚群参与IDDM的机制 具有优先呈递某些胰腺B细胞抗原的能力， 自身反应性MHC II类限制性T细胞。具体目标1是确定 介导该过程的B淋巴细胞必须表达免疫球蛋白（IG） 能够特异性捕获B细胞自身抗原的分子，如果是这样， 这些致糖尿病的APC通过耐受诱导缺陷产生。这些问题 将通过使用表达重排的IG转基因的NOD小鼠来解决。 另一个未知因素是NOD B淋巴细胞是否也表现出任何Idd基因 APC介导的耐受性诱导中的受控缺陷， 糖尿病性T细胞的初始发育。抗性变体的表达 在所有APC亚型上的某些MHC Idd基因的表达阻断了APC的发育或 致糖尿病性T细胞的功能活化。目标2：确定 赋予IDDM抗性的特定的MHC基因组必须表达在 使NOD T细胞对胰腺B细胞耐受特异性APC亚型 抗原这些研究将利用NOD小鼠和相关菌株， 特定APC亚群上各种MHC基因的IDDM抗性变体。非mhc 这些基因也有助于NOD B淋巴细胞的致糖尿病APC活性。 具体目标3是确定非MHC基因的作用机制， NOD小鼠中具有致糖尿病APC活性的B淋巴细胞的发育。 这个问题将通过嵌合系统解决，其中NOD T细胞可以 仅在选定的B淋巴细胞群存在下才成熟和发挥功能。 总的来说，拟议的研究将描述B 淋巴细胞对T细胞介导的 自身免疫性胰岛素依赖型糖尿病

DESCRIPTION: (Adapted from the Investigator's abstract): T cell mediated autoimmune IDDM results from interactions between multiple susceptibility (Idd) genes located within and outside of the MHC. In NOD mice some of these polygenic interactions engender diabetogenic T cell development by reducing the ability of hematopoietically derived antigen presenting cells (APC) to activate various immunoregulatory functions. Subpopulations of APC include B-lymphocytes, macrophages, and dendritic cells. To partially address which APC subpopulations contribute to IDDM, the investigators produced NOD mice made deficient in B lymphocytes by a functionally inactivated Ig mu gene. These B lymphocyte deficient NOD.Ig mu null mice are IDDM resistant. Their overall objective is to delineate the mechanism(s) by which B lymphocytes contribute to the development of T cell mediated autoimmune 1DDM. They have found one mechanism that B lymphocytes contribute to IDDM is as a subpopulation of APC with a preferential ability to present certain pancreatic B cell antigens to autoreactive MHC class II restricted T cells. Specific aim 1 is to determine if the B lymphocytes mediating this process must express immunoglobulin (Ig) molecules capable of specifically capturing B cell autoantigens, and if so, do these diabetogenic APC arise through tolerance induction defects. These issues will be addressed through use of NOD mice expressing rearranged Ig transgenes. Another unknown factor is if NOD B lymphocytes also manifest any Idd gene controlled defects in APC mediated tolerance induction that underlie the initial development of diabetogenic T cells. Expression of resistance variants of certain MHC Idd genes on all APC subtypes blocks the development or functional activation of diabetogenic T cells. Aim 2 is to determine if particular sets of MHC genes that confer IDDM resistance must be expressed on specific APC subtypes to render NOD T cells tolerant to pancreatic B cell antigens. These studies will utilize NOD mice and related strains that express IDDM resistance variants of various MHC genes on specific APC subsets. Non-MHC genes also contribute to the diabetogenic APC activity of NOD B lymphocytes. Specific aim 3 is to determine the mechanisms by which non-MHC genes contribute to the development of B-lymphocytes with diabetogenic APC activity in NOD mice. This issue will be addressed through a chimeric system in which NOD T cells can only mature and function in the presence of selected B lymphocyte populations. Collectively, the proposed studies will delineate mechanisms by which B lymphocytes make critical contributions to the development of T cell mediated autoimmune IDDM.