We have studied a primate model for liver-directed gene transfer and demonstrated an active immune response to the adenovirus vector with acute hepatitis in rhesus monkeys (Macaca mulatta). In order to define the mechanism of acute hepatitis, liver biopsy specimens of 6 rhesus monkeys were studied by immunohistochemical staining (ABC method) with antibodies to lymphocyte phenotypes and HLA antigens. The monkeys developed a mild to moderate acute hepatitis 1 to 3 weeks after intravenous or intrabiliary injection of first generation replication-defective adenovirus carrying a reporter gene. This was accompanied by adenovirus-mediated T-cell proliferation and neutralizing antibodies to adenovirus. Increased numbers of CD3- and CD4-positive T-lymphocytes were detected in the diseased livers, while B-lymphocytes were absent. Hepatocytes demonstrated increased expression of a2 microglobulin and of HLA class II antigens in the plasma membranes. To limit the host immune response, 4 animals were immunosuppressed by cyclophosphamide/prednisone and then infused with replication-defective adenovirus via the portal vein or the saphenous vein. The development of acute hepatitis and the accompanying immune abnormalities were delayed in these monkeys until after discontinuation of immunosuppressive therapy. There appears to be a strong T-cell- mediated gene transfer which may be delayed by immunosuppressive therapy. A better understanding of the immune response to adenovirus may lead to rational strategies for more effective adenovirus-mediated liver-directed gene therapy.
Showing the most recent 10 out of 352 publications
