PROLONGED SURVIVAL OF PANCREATIC-ISLET ALLOGRAFTS MEDIATED BY ADENOVIRUS IMMUNOREGULATORY TRANSGENES

The adenovirus (Ad) early region 3 (E3) genes code for at least four p roteins that inhibit the host immune responses mediated by cytotoxic T lymphocytes and tumor necrosis factor alpha. To evaluate the potentia l use of these immunoregulatory viral functions in facilitating alloge neic cell transplantation, the Ad E3 genes were expressed in pancreati c beta cells in transgenic mice under control of the rat insulin II pr omoter, Transgenic H-2(b/d) (C57BL/6 x BALB/c) islets, expressing the Ad E3 genes, remained viable for at least 94 days after transplantatio n under the kidney capsule of BALB/c (H-2(d)) recipients. Nontransgeni c H-2(b/d) control islets were rejected as anticipated between 14 and 28 days, Histological analysis of the transplanted transgenic islets r evealed normal architecture, Immunohistochemical studies with antisera to islet hormones revealed the presence of both beta and non-beta isl et cells, suggesting a propagation of the immunosuppressive effect of Ad proteins from beta cells to other islet cells. The use of viral gen es, which have evolved to regulate virus-host interactions, to immunos upress the antigenicity of donor transplant tissue suggests additional ways for prolonging allograft survival, In addition, these findings h ave implications for designing Ad vectors for gene therapy.