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.
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