Induction of glutamic acid decarboxylase 65-specific Th2 cells and suppression of autoimmune diabetes at late stages of disease is epitope dependent

Peptide-based immunotherapy is one strategy by which to selectively suppres s the T cell-mediated destruction of beta cells and treat insulin-dependent diabetes mellitus (IDDM). Here, we investigated whether a panel of T cell epitopes derived from the beta cell autoantigen glutamic acid decarboxylase 65 (GAD65) differ in their capacity to induce Th2 cell function in nonobes e diabetic (NOD) mice and in turn prevent overt IDDM at different preclinic al stages of disease development. The panel consists of GAD65-specific pept ides spanning aa 217-236 (p217), 247-265 (p247), 290-309 (p290), and 524-54 3 (p524), Our studies revealed that all of the peptides effectively prevent ed insulitis and diabetes when administered to NOD mice before the onset of insulitis, In contrast, only a mixture of p217 and p290 prevented progress ion of insulitis and overt IDDM in NOD mice exhibiting extensive beta cell autoimmunity. Immunization with the GAD65-specific peptides did not block I DDM development in NOD mice deficient in IL-4 expression, These findings de monstrate that GAD65-specific peptide immunotherapy effectively suppresses progression to overt IDDM, requires the production of IL-4, and is dependen t on the epitope targeted and the extent of preexisting beta cell autoimmun ity in the recipient.