LOCAL EXPRESSION OF TRANSGENE ENCODED TNF-ALPHA IN ISLETS PREVENTS AUTOIMMUNE DIABETES IN NONOBESE DIABETIC (NOD) MICE BY PREVENTING THE DEVELOPMENT OF AUTO-REACTIVE ISLET-SPECIFIC T-CELLS

Lately, TNF alpha has been the focus of studies of autoimmunity; its r ole in the progression of autoimmune diabetes is, however, still uncle ar. To analyze the effects of TNF alpha in insulin-dependent diabetes mellitus (IDDM), we have generated nonobese diabetic (NOD) transgenic mice expressing TNF alpha under the control of the rat insulin II prom otor (RIP). In transgenic mice, TNF alpha expression on the islets res ulted in massive insulitis, composed of CD4+ T cells, CD8+ T cells, an d B cells. Despite infiltration of considerable number of lymphoid cel ls in islets, expression of TNF alpha protected NOD mice from IDDM. To determine the mechanism of TNF alpha action, splenic cells from contr ol NOD and RIP-TNF alpha mice were adoptively transferred to NOD-SCID recipients. In contrast to the induction of diabetes by splenic cells from control NOD mice, splenic cells from RIP-TNF alpha transgenic mic e did not induce diabetes in NOD-SCID recipients. Diabetes was induced however, in the RIP-TNF alpha transgenic mice when CD8+ diabetogenic cloned T cells or splenic cells from diabetic NOD mice were adoptively transferred to these mice. Furthermore, expression of TNF alpha in is lets also downregulated splenic cell responses to autoantigens. These data establish a mechanism of TNF alpha action and provide evidence th at local expression of TNF alpha protects NOD mice from autoimmune dia betes by preventing the development of autoreactive islet-specific T c ells.