Loss of pancreatic islet tolerance induced by β-cell expression of interferon-γ

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Abstract
INTERFERON-γ (IFN-γ) is produced during the response to infection and participates in immunostimulatory events. We have previously reported the induction of diabetes in transgenic mice (ins-IFN-γ) in which the expression of the lymphokine IFN-γ is directed by the insulin promoter1. This diabetes is a result of the progressive destruction of pancreatic islets that occurs with the influx of inflammatory cells. Here we demonstrate that this islet cell loss is mediated by lymphocytes, that engrafted histocompat-ible islets are destroyed, and that lymphocytes from the transgenic mice are cytotoxic to normal islets in vitro. These results indicate that the pancreatic expression of IFN-γ can result in a loss of tolerance to normal islets, consistent with its role as an inducer of costimulatory activity2,3, which is essential for lymphocyte activation during an immune response.