NATURALLY PROCESSED T-CELL EPITOPES FROM HUMAN GLUTAMIC-ACID DECARBOXYLASE IDENTIFIED USING MICE TRANSGENIC FOR THE TYPE-1 DIABETES-ASSOCIATED HUMAN MHC CLASS-II ALLELE, DRB1-ASTERISK-0401

The identification of class II binding peptide epitopes from autoimmun e disease-related antigens is an essential step in the development of antigen-specific immune modulation therapy. In the case of type I diab etes, T cell and B cell reactivity to the autoantigen glutamic acid de carboxylase 65 (GAD65) is associated with disease development in human s and in nonobese diabetic (NOD) mice. In this study, we identify two DRB10401-restricted T cell epitopes from human GAD65, 274-286, and 11 5-127. Both peptides are immunogenic in transgenic mice expressing fun ctional DRB10401 MHC class II molecules but not in nontransgenic litt ermates. Processing of GAD65 by antigen presenting cells (APC) resulte d in the formation of DRB10401 complexes loaded with either the 274-2 86 or 115-127 epitopes, suggesting that these naturally derived epitop es may be displayed on APC recruited into pancreatic islets. The prese ntation of these two T cell epitopes in the islets of DRB10401 indivi duals who are at risk for type 1 diabetes may allow for antigen-specif ic recruitment of regulatory cells to the islets following peptide imm unization.