Glutamic acid decarboxylase T lymphocyte responses associated with susceptibility or resistance to type I diabetes: analysis in disease discordant human twins, nonobese diabetic mice and HLA-DQ transgenic mice

Glutamic acid decarboxylase (GAD(65)) has been implicated as a targeted ser f antigen in the immune destruction of pancreatic beta cells. T cell respon ses to GAD(65) peptides have been detected in both patients with type I dia betes and in the non-obese diabetic (NOD) mouse. To establish which GAD65 e pitopes are important in the immunopathogenesis of disease we initially com pared T cell responses to GAD(65) epitopes in conditions of disease suscept ibility and protection. T cell responses to GAD(65) peptides were measured in monozygotic twin pairs selected on the basis of disease discordance and T cell recognition of immunogenic regions of GAD(65). Peptides of interest were then used to immunize susceptible NOD mice and H2-E transgenic NOD mic e which are protected from diabetes. A differential response to the epitope GAD(65) 521-535 discriminated diabetic from non-diabetic human twins as we ll as susceptible from protected mice. This epitope as well as GAD 505-519 induces T cell responses despite binding the type I diabetes associated HLA -DQA1*0301/DQB1*0302 product with low affinity. Since DO-restricted T cell responses are difficult to study in humans, HLA-DQ8 transgenic mice were th en used: GAD epitopes 521-535 and 505-519 induced responses in DQ8 transgen ic mice and T cell lines were established. Long-term T cell lines against G AD 505-519 were HLA-DQ restricted, and responded to peptide with a strong I FN-gamma and IL-10 response. The findings implicate GAD 521-535 as a possib le target peptide in pathogenesis and are compatible with a model whereby s elf-reactive T cells specific for low-affinity peptide-MHC complexes may es cape thymic negative selection.