Type 1 diabetes or 'IDDM' is a severe autommune disease afflicting hundreds of thousands of Americans. It is characterized by an attack on the pancreas, that abrogates insulin production. While the attacking infiltrate comprises multiple cell types, T cells are critical. The precise target of the T cells may also be manifold, but among them, central importance is attached to glutamic acid decarboxylase (GAD), particularly the 65kD form, GAD65. Experimental administration of recombinant GAD to non obese diabetic (NOD) mice that are highly predisposed to IDDM, ameliorated the attack on the pancreas, and subsequent disease development. These and other results have prompted the Food and Drug Administration to review the idea of administering GAD to individuals at high risk for developing IDDM. This notwithstanding, there is currently very little understanding of autoreactivity to GAD. In particular, it remains unclear why NOD mice and (by extrapolation) humans predisposed to IDDM fail to develop tolerance to GAD naturally. The characterization of the autoreactivity to GAD65 can be facilitated by the development of novel strains of NOD mouse in which GAD65 and/or T cell antigen T cell antigen receptors to GAD65, are expressed in unusual patterns. Such mice also facilitate the study of how T cells autoreactive to GAD can be regulated by other lymphocytes, and by the microbial environment. The development of such mice is described in the proposal and the case made for their detailed study.
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