WIDESPREAD EXPRESSION OF AN AUTOANTIGEN-GAD65 TRANSGENE DOES NOT TOLERIZE NONOBESE DIABETIC MICE AND CAN EXACERBATE DISEASE

Glutamic acid decarboxylase (GAD)65 is a pancreatic beta cell autoanti gen implicated as a target of T cells that initiate and sustain insuli n-dependent diabetes mellitus (IDDM) in humans and in non-obese diabet ic (NOD) mice. In an attempt to establish immunological tolerance towa rd GAD65 in NOD mice, and thereby to test the importance of GAD in IDD M, we generated three lines transgenic for murine GAD65 driven by a ma jor histocompatibility complex class I promoter. However, despite wide spread transgene expression in both newborn and adult mice, T cell tol erance was not induced, Mononuclear cell infiltration of the islets (i nsulitis) and diabetes were at least as bad in transgenic mice as in n ontransgenic NOD mice, and in mice with the highest level of GAD65 exp ression, disease was exacerbated. In contrast, the same transgene intr oduced into mouse strain, FvB, induced neither insulitis nor diabetes, and T cells were tolerant to GAD, Thus, the failure of NOD mice to de velop tolerance toward GAD65 reflects at minimum a basic defect in cen tral tolerance, not seen in animals not predisposed to IDDM, Hence, it may not be possible experimentally to induce full tolerance toward GA D65 in prediabetic individuals. Additionally, the fact that autoimmune infiltration in GAD65 transgenic NOD mice remained largely restricted to the pancreas, indicates that the organ-specificity of autoimmune d isease is dictated by tissue-specific factors in addition to those dir ecting autoantigen expression.