CYTOTOXIC T-CELLS SPECIFIC FOR GLUTAMIC-ACID DECARBOXYLASE IN AUTOIMMUNE DIABETES

Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease th at results in the destruction of the pancreatic islet beta cells. Glut amic acid decarboxylase (GAD) has been recently indicated as a key aut oantigen in the induction of IDDM in nonobese diabetic mice. In human diabetes, the mechanism by which the beta cells are destroyed is still unknown. Here we report the first evidence for the presence of GAD-sp ecific cytotoxic T cells in asymptomatic and recent diabetic patients. GAD65 peptides displaying the human histocompatibility leukocyte anti gen (HLA)-A()0201 binding motif have been synthesized. One of these p eptides, GAD114-123, binds to HLA-A0201 molecules in an HLA assembly assay. Peripheral blood mononuclear cells from individuals with precli nical IDDM, recent-onset IDDM, and from healthy controls were stimulat ed in vitro with the selected peptide in the presence of autologous an tigen-presenting cells. In three cases (one preclinical IDDM and two r ecent-onset IDDM), we detected specific killing of autologous antigen- presenting cells when incubated with GAD114-123 peptide or when infect ed with a recombinant vaccinia virus expressing GAD65. These patients were the only three carrying the HLA-A0201 allele among the subjects studied. Our finding suggests that GAD-specific cytotoxic T lymphocyte s may play a critical role in the initial events of IDDM.