ACTIVATION OF CD8(-LYMPHOCYTES IN INSULIN-DEPENDENT DIABETES-MELLITUS() T)

Insulin-dependent diabetes mellitus (IDDM) is a T-cell-mediated autoim mune disease directed against the insulin-secreting beta cells of the islets of Langerhans of the pancreas. We have previously shown that in organ-specific autoimmune diseases, Graves' disease (GD), and IDDM, t he antigen that is specific for each of these disorders (i.e., TSH rec eptor for GD, glutamic acid decarboxylase-65 (GAD65) for IDDM) does no t activate the disease-specific CD8(+) cells as fully as CD8(+) cells from normal persons. In order to identify the specific antigen respons ible for triggering or maintaining autoimmunity in patients afflicted with the disease, we have studied the effects of islet (beta) cell-spe cific antigens GAD65, insulin, pancreatic antigen (P69), T cell epitop e 69 (Tep69), and a milk-derived bovine serum albumin (BSA)-peptide-AB BOS (pre-BSA positions 157-169) on the activation of CD8(+) T lymphocy tes in IDDM patients. We compared the patterns of T cell activation wi th those mediated by an irrelevant peptide antigen, P348 (amino-termin al region of human cardiac myosin light chain-1), and also tetanus tor oid. We also studied the responses of CD8(+) T lymphocytes to these ID DM-relevant and -irrelevant antigens in Hashimoto's thyroiditis patien ts (HT), rheumatoid arthritis patients (RA), and normal control subjec ts (N) to compare the pattern of responses in the other autoimmune dis eases. Activation of lymphocytes was monitored by measuring the expres sion of the activation molecule-major histocompatibility complex class II antigen (KLA-DR) on the surfaces of CD8(+) T lymphocytes by flow c ytometry. Peripheral blood mononuclear cells (PBMC) obtained from 14 p atients with IDDM, 14 N, 14 with HT, and 13 with RA were cultured for 7 days in the presence or absence of antigens. The stimulation index ( SI) of activation of the lymphocytes was determined. When the response of CD8(+) T lymphocytes of IDDM patients to each of the IDDM-relevant antigens was compared to that of the irrelevant antigen, only GAD65 a nd ABBOS showed a significantly reduced activation compared to P348 an d tetanus toxoid. Other relevant antigens, insulin, P69, and Tep69, di d not show any significant differences in their SI compared to those o f the irrelevant antigens. In the N, HT, and RA groups, there was no s ignificant difference in the SI of the responses of CD8(+) cells to an y of the relevant antigens compared to that of the irrelevant antigens . Moreover, CD8(+) T lymphocytes of IDDM patients showed a significant ly lower activation by GAD65 than those from N, HT, and RA. In conclus ion, our data suggest that CD8(+) T lymphocytes of IDDM. patients but not those from N, HT, and RA groups have specifically reduced potentia l for activation in response to GAD65 but not to insulin, P69, and Tep 69, whereas ABBOS exerts a less well-defined reductive effect on the a ctivation of CD8(+) lymphocytes of IDDM patients. Since CD8(+) cells h ave been shown to contain suppressor activity, our data support the no tion that a disease-specific defect in GAD65 autoantigenic induction o f suppressor T lymphocytes may be important in the pathogenesis of IDD M. (C) 1997 Academic Press.