TY - JOUR
T1 - Prolonged survival of pancreatic islet allografts mediated by adenovirus immunoregulatory transgenes
AU - Efrat, Shimon
AU - Fejer, Gyorgy
AU - Brownlee, Michael
AU - Horwitz, Marshall S.
PY - 1995/7/18
Y1 - 1995/7/18
N2 - The adenovirus (Ad) early region 3 (E3) genes code for at least four proteins that inhibit the host immune responses mediated by cytotoxic T lymphocytes and tumor necrosis factor α. To evaluate the potential use of these immunoregulatory viral functions in facilitating allogeneic cell transplantation, the Ad E3 genes were expressed in pancreatic beta cells in transgenic mice under control of the rat insulin II promoter. Transgenic H- 2(b/d) (C57BL/6 x BALB/c) islets, expressing the Ad E3 genes, remained viable for at least 94 days after transplantation under the kidney capsule of BALB/c (H-2(d)) recipients. Nontransgenic H-2(b/d) control islets were rejected as anticipated between 14 and 28 days. Histological analysis of the transplanted transgenic islets revealed normal architecture. Immunohistochemical studies with antisera to islet hormones revealed the presence of both β and non-β islet cells, suggesting a propagation of the immunosuppressive effect of Ad proteins from β cells to other islet cells. The use of viral genes, which have evolved to regulate virus-host interactions, to immunosupress the antigenicity of donor transplant tissue suggests additional ways for prolonging allograft survival. In addition, these findings have implications for designing Ad vectors for gene therapy.
AB - The adenovirus (Ad) early region 3 (E3) genes code for at least four proteins that inhibit the host immune responses mediated by cytotoxic T lymphocytes and tumor necrosis factor α. To evaluate the potential use of these immunoregulatory viral functions in facilitating allogeneic cell transplantation, the Ad E3 genes were expressed in pancreatic beta cells in transgenic mice under control of the rat insulin II promoter. Transgenic H- 2(b/d) (C57BL/6 x BALB/c) islets, expressing the Ad E3 genes, remained viable for at least 94 days after transplantation under the kidney capsule of BALB/c (H-2(d)) recipients. Nontransgenic H-2(b/d) control islets were rejected as anticipated between 14 and 28 days. Histological analysis of the transplanted transgenic islets revealed normal architecture. Immunohistochemical studies with antisera to islet hormones revealed the presence of both β and non-β islet cells, suggesting a propagation of the immunosuppressive effect of Ad proteins from β cells to other islet cells. The use of viral genes, which have evolved to regulate virus-host interactions, to immunosupress the antigenicity of donor transplant tissue suggests additional ways for prolonging allograft survival. In addition, these findings have implications for designing Ad vectors for gene therapy.
KW - diabetes
KW - major histocompatibility complex
KW - transplantation
KW - tumor necrosis factor
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U2 - 10.1073/pnas.92.15.6947
DO - 10.1073/pnas.92.15.6947
M3 - Article
C2 - 7624350
AN - SCOPUS:0029125671
SN - 0027-8424
VL - 92
SP - 6947
EP - 6951
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 15
ER -