CELLULAR AND MOLECULAR MECHANISMS FOR THE INITIATION AND PROGRESSION OF BETA-CELL DESTRUCTION RESULTING FROM THE COLLABORATION BETWEEN MACROPHAGES AND T-CELLS

Insulin-dependent diabetes mellitus (IDDM) is caused by the progressiv e autoimmune destruction of insulin-producing pancreatic beta cells. A lthough the pathogenesis of autoimmune IDDM has been extensively studi ed, the precise mechanisms involved in the initiation and progression of beta cell destruction remain unclear. Animal models used in the stu dy of IDDM, such as the BioBreeding (BE) rat and the nonobese diabetic (NOD) mouse, have greatly enhanced our understanding of the pathogeni c mechanisms involved in this disease. In these animals, macrophages a nd/or dendritic cells are the first cell types to infiltrate the pancr eatic islets. Macrophages must be involved in the pathogenesis of IDDM early on, since inactivation of macrophages results in the near-compl ete prevention of insulitis and diabetes in both NOD mice and BE rats. The presentation of beta cell-specific autoantigens by macrophages an d/or dendritic cells to CD4+ T helper cells, in association with MHC c lass II molecules, is considered the initial step in the development o f autoimmune IDDM. The activated macrophages secrete IL-12, which stim ulates Th1 type CD4+ T cells. The CD4+ T cells secrete IFN-gamma and I L-2. IFN-gamma activates other resting macrophages, which, in turn, re lease cytokines, such as IL-1 beta, TNF-alpha, and free radicals, whic h are toxic to beta cells. During: this process, IL-2 and other cytoki nes induce the migration of CD8+ peripheral T cells to the inflamed is lets, perhaps by inducing the expression of a specific homing receptor . The precytotoxic CD8+ T cells that bear beta cell-specific autoantig en receptors differentiate into cytotoxic effector T cells upon recogn ition of the beta cell-specific peptide bound to MHC class I molecules in the presence of beta cell-specific CD4+ T helper cells. The cytoto xic CD8+ T cells then effect beta cell damage by releasing perforin an d granzyme, and by Fas-mediated apoptosis. In this way, macrophages, C D4+ T cells, and CD8+ T cells synergistically destroy beta cells, resu lting in the onset of autoimmune IDDM.