Endogenous immune response to glutamic acid decarboxylase (GAD67) in NOD mice is modulated by adjuvant immunotherapy

We have shown that immunization of non-obese diabetic (NOD) mice with adjuv ants (CFA or BCG) prevents the onset of diabetes by induction of regulatory cells. Since autoimmune responses to glutamic acid decarboxylase (GAD) are up-regulated in insulin-dependent diabetes mellitus (IDDM), in this study GAD67-specific antibody, T cell proliferation and lymphokine production pat terns were analysed in the adjuvant-treated mice to characterize the regula tory mechanisms underlying the protection. We used both spontaneous diabete s and syngeneic islet transplantation models in NOD mice. Protect:ion again st spontaneous diabetes and prevention of syngeneic islet graft rejection b y CFA or BCG treatment was found to be accompanied by the production of lon g lasting and high titre anti-GAD67 antibody of IgG1 isotype in the sera. U pon in vitro stimulation with GAD67, draining lymph node and spleen cells f rom CFA-immunized NOD mice or syngeneic islet-grafted and BCG-protected NOD mice produced much more IL-4, whereas there was no significant change in I FN-gamma production. The strong early T cell proliferative response to GAD6 7 in CFA or BCG-immunized NOD mice was followed by a law or unresponsivenes s state. Taken together, these results suggest a shift in Th1/Th2 balance i n the GAD67-specific endogenous immune response to a change in Th2 levels a fter adjuvant treatment. We postulate that the protective effect of CFA or BCG is due to the diversion of GAD-specific endogenous cellular immune resp onse to a non-pathogenic humoral response. (C) 1998 Academic Press.