T-CELL PROLIFERATIVE RESPONSES TO GLUTAMIC-ACID DECARBOXYLASE-65 IN IDDM ARE NEGATIVELY ASSOCIATED WITH HLA DR3 4/

Based on studies in spontaneously non-obese diabetic (NOD) mice, it ha s been suggested that the Mr 65.000 isoform of glutamic acid decarboxy lase (GAD(65)) is of major importance in the pathogenesis of insulin-d ependent diabetes mellitus (IDDM). In humans, antibodies to GAD(65) ar e present before and at onset of the disease and in vitro T cell react ivity to GAD has also been reported. To further characterize the T cel l recognition of GAD(65), we incubated peripheral blood mononuclear ce lls from 45 newly diagnosed IDDM patients with purified recombinant hu man islet GAD(65) and correlated the proliferative response with HLA D R haplotype and the presence of GAD(65) autoantibodies. Fifty healthy individuals were studied as controls. Of the patients, 49% showed prol iferative responses to GAD(65) in contrast to only 4% of the controls. T cell proliferation to GAD(65) was significantly more frequent in pa tients not being HLA DR3/4 heterozygous(19/29, 66%) as compared to HLA DR3/4 heterozygous patients (3/16, 19%) (p < 0.01). The difference wa s most pronounced in females with 64% (9/14) of the HLA non-DR3/4 pati ents being positive compared to none (0/6) of the HLA DR3/4 patients ( p < 0.05). The overall frequency of GAD(65) autoantibodies was 71% (32 /45) with a similar distribution between patients with HLA DR3/4 (10/1 6, 63%) and HLA non-DR 3/4 (22/29, 76%). There was no correlation betw een levels of the T and B cell responses to GAD(65) (r = 0.24). In con clusion, we find a proliferative T cell response to GAD(65) in approxi mately 50% of recent onset IDDM patients and unexpectedly find the maj ority of responders to be HLA non-DR3/4 heterozygous patients. No diff erence was observed in B cell responsiveness between the two HLA group s.