MHC CLASS I-RESTRICTED CYTOTOXIC T-LYMPHOCYTES TO VIRAL-ANTIGENS DESTROY HEPATOCYTES IN MICE INFECTED WITH E1-DELETED RECOMBINANT ADENOVIRUSES

The use of E1-deleted recombinant adenoviruses in gene therapy has consistently been associated with transient gene expression and inflammation due to immune-based destruction of the infected cells. We have used murine models of adenovirus-mediated gene transfer to liver to Investigate these immunologic mechanisms. Adoptive transfer experiments, as well as studies involving genetic knockout mice, confirmed the original hypothesis that cell-mediated immunity induced by E1-deleted adenovirus destroyed transgene-expressing hepatocytes and defined MHC class I-restricted CD8(+) cytolytic lymphocytes as the primary immune effecters for hepatocyte destruction. Responses mediated by CD4(+) cells per se were insufficient to mediate destruction of hepatocytes in vivo, despite the activation of virus-specific T helper cells of Th1 subsets. A better understanding of the response of the host to in vivo gene therapy is important in evaluating its usefulness in humans.