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Despite the widely accepted view of the liver as an immunoprivileged tissue, purified allogeneic liver parenchymal cells delivered to the liver of a recipient mouse are highly antigenic. A functional transgenic model of hepatocyte transplantation in mice is used to explore host immune responses to allogeneic hepatocytes. Transplanted hepatocytes expressing human alpha-1-antitrypsin (hA1AT) are monitored for survival by the secretion of the transgene product hA1AT. Transplantation of transgenic hepatocytes into syngeneic or immunoincompetent severe combined immunodeficiency disease (SCID) mice results in indefinite hepatocellular allograft survival. However, transplantation of transgenic hepatocytes into allogeneic hosts results in rapid hepatocyte rejection. This rejection response is associated with prominent delayed type hypersensitivity responses to cellular alloantigen but minimal donor-reactive humoral immunity. Hepatocyte rejection is not controlled by host treatment with anti-CD4 mAb despite the ability of the same treatment regimen to produce indefinite survival of donor-matched heart allografts. Host immune responses to allogeneic hepatocytes utilize CD40L/CD40 but not CD28/B7 co-stimulation, unlike the activation of both of these systems in responses to other allografts. Furthermore, C57BL/6 mice which have been induced by anti-CD4 mAb or gallium nitrate treatment to accept heart allografts promptly reject donor-matched transgenic hepatocytes. Studies in reconstituted SCID, CD4 knockout (KO), and CD8 KO mice demonstrate that hepatocyte rejection can be initiated independently by either CD4+ T cells or CD8+ T cells, which again diverges from what has been observed for most other types of allografts. This may account for the relative resistance to immunoprotection for hepatocellular allografts with conventional immunosuppressive agents and to immunoregulatory states induced by other allografts. Three models of hepatocyte rejection are discussed.