Insulin dependent diabetes mellitus (IDDM) is thought to be an autoimmune disease mediated by T lymphocytes. Activation of T cells requires two stimulatory signals. The first is provided by the interaction of the antigen receptor with the appropriate antigen in the context of self MHC molecule. The second, non-cognate interaction, involves interactions between ligands on the T cell surface and on antigen presenting cells (APCs). We have found that the non-cognate interaction between the CD28 family of molecules on T cells and B7 molecules on APC and other cells is involved in the pathogenesis of IDDM in the NOD mouse. Treatment with a soluble CD28/B7 antagonist. CTLA41g. can prevent IDDM and IDDM is worsened when animals are treated with monoclonal antibodies (mAbs) against B7-1. The purpose of this study is to understand the role of CD28/B7 interactions in the pathophysiology of IDDM. To determine the mechanism of CTLA4Ig mediated suppression of NOD diabetes, we will study the effects of the various mAbs and antagonists on the phenotype and function of T cells that invade the islets following treatment but do not cause diabetes. The ability of cells from these animals to respond to islet antigens will be tested. Adoptive transfer experiments will be conducted to determine the effects of CTLA4Ig and B7-1 and anti-B7-2 mAbs on T cells and islets in NOD mice. We will study the effects of these reagents on T cells in a transgenic mouse the expresses a T cell receptor from a diabetogenic CD4+ T cell clone on the majority of its peripheral T cells to determine the fate of islet antigen reactive T cells that are treated with CTLA4-Ig. To determine the molecular mechanisms controlling anti-B7-1-mediated exacerbation of NOD diabetes, we will examine the ability of non-activating forms of antiB7-1 mAbs to accelerate disease and test the ability of anti- B7 mAb to precipitate IDDM in animals with insulitis that do not develop IDDM such as NOR or B6NOD TCR transgenic mice. Functional studies of T cells and APCs from anti-B7-1 mAb-treated mice will be done to determine whether anti-B7-1 mAb affects T cells or antigen presenting cells in NOD. Finally, using a genetic approach to rapidly fix IDDM susceptibility genes, we will breed NOD mice in which CD28. CTLA-4. B7-2 have been genetically disrupted or which have a truncated B7-1 molecule in order to understand the role of each ligand in the d envelopment of IDDM in this model. The experiments proposed will develop a model for the roles of these co- stimulatory receptors and ligands in regulating autoimmune diabetes. These molecules appear to have an essential role in regulating IDDM in the NOD mouse. Understanding these roles is an essential pre-requisite for realizing the clinical potential for this class of reagents.
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