The NOD mouse provides one of the best animal models for autoimmune diabetes. TNF, when administered to adult animals in pharmacologic doses, mediates protection from autoimmune diabetes in NOD mice, and exacerbates disease when administered neonatally. Islet-specific transgene encoded TNF mediates inflammatory infiltrates in normal mice, but surprisingly the investigators have shown that it is also protective against the development of autoimmune diabetes. In this project they will elucidate the mechanism whereby islet-specific transgene encoded TNF on an NOD background prevents diabetes. They will determine whether the mechanism whereby TNF prevents the anti-islet autoimmune response is mediated by the elimination or inactivation of autoaggressive T cells. They will also test for possible immune deviation of the anti-islet response, for example, from a TH1-like to a TH2-like response. They will test whether protection is mediated by dominant regulatory mechanisms by performing adoptive transfer studies. To facilitate these analyses they will utilize T-cell clones in adoptive transfer experiments, and T cells from TCR transgenic mice carrying either CD4 or CD8 islet-specific T cells. Finally, they will determine whether TNF expression initiating early in the life of the NOD mouse, protects or exacerbates from disease, and, if exacerbation is observed, they will determine the mechanism by which that occurs.
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