EFFECT OF ADENOVIRUS E3 IMMUNOREGULATORY PROTEIN ON ALLOGENIC TRANSPLANTATION

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Human adenoviruses (Ads) encode a number of proteins that modulate the host responses against virus-infected cells. These proteins, whose genes are clustered in the early region 3 (E3) transcription unit, can (1) control transport of the class I major histocompatibility complex (MHC) heavy chain from the endoplasmic reticulum (ER) to the cell surface and (2) inhibit cytolysis induced by tumor necrosis factor alpha (TNFalpha). We postulated that the anti-class I MHC and anti-TNF effects of the Ad E3 genes may be used to facilitate allogenic pancreatic beta-cell transplantation and prevent autoimmune diabetes. Experiments have been performed in transgenic mice carrying the entire Ad2 E3 transcription region behind the rat insulin promoter (RIP) to test these hypothesis. Both tolerization to long-term allogeneic transplantation and prevention of lymphocytic choriomeningitis virus (LCMV)-induced autoimmune diabetes have been achieved in the presence of the Ad E3 transgenes expressed in islets. Encouraged by these initial results, we wish to extend these observations into new area of investigation by studying the contributions of individual Ad E3 gene products in the transplantation and LCMV models as well as introduce the Ad E3 immunoregulatory gene functions into the islets of nonobese diabetic (NOD) mice. The Ad E3 genes will also be inserted into a conditionally immortalized and growth controlled murine beta-cell line for the long term correction of diabetes by allogeneic transplantation.