ANTIGEN PRESENTING CELL DEFECTS IN AUTOIMMUNE DIABETES

描述（改编自研究者摘要）：本项目提出

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.