MODULATING AUTOIMMUNE RESPONSES TO GAD INHIBITS DISEASE PROGRESSION AND PROLONGS ISLET GRAFT-SURVIVAL IN DIABETES-PRONE MICE

In nonobese diabetic (NOD) mice, beta-cell reactive T-helper type 1 (T h1) responses develop spontaneously and gradually spread, creating a c ascade of responses that ultimately destroys the beta-cells. The diver sity of the autoreactive T-cell repertoire creates a major obstacle to the development of therapeutics. We show that even in the presence of established Th1 responses, it is possible to induce autoantigen-speci fic anti-inflammatory Th2 responses. Immune deviation of T-cell respon ses to the beta-cell autoantigen glutamate decarboxylase (GAD65), indu ced an active form of self-tolerance that was associated with an inhib ition of disease progression in prediabetic mice and prolonged surviva l of syngeneic islet grafts in diabetic NOD mice. Thus, modulation of autoantigen-specific Th1/Th2 balances may provide a minimally invasive means of downregulating established pathogenic autoimmune responses.