Immunologic considerations for therapeutic strategies utilizing allogeneichepatocytes: Hepatocyte-expressed membrane-bound major histocompatibility complex class I antigen sensitizes while soluble antigen suppresses the immune response in rats

Understanding the immunologic effects of hepatocytes is critical because of the potential to use these cells for bioartificial livers, as a vehicle fo r gene transfer, and as a means to induce donor-specific immunosuppression in organ transplantation, However, this understanding is complicated by the fact that hepatocytes express membrane-bound and soluble forms of major hi stocompatibility complex (MHC) class I antigen, each with the potential to induce different immune responses. In the present study we first determined the immunologic effect of normal donor-derived hepatocytes in a rat heart transplant model. We then used ex vivo hepatocyte gene transfer to examine the immunologic effects of different forms of hepatocyte-expressed MHC clas s I antigen, Results showed that intrasplenic injection of purified, donor- strain-specific hepatocytes into recipients primes alloimmunity, as evidenc ed by acceleration of heart allograft rejection. Interestingly, injection o f autologous hepatocytes transfected ex vivo with DNA encoding only membran e-bound donor MHC class I antigen (RT1.A(a)) also accelerated allograft rej ection. However, hepatocytes transfected to express only secreted donor MHC antigen prolonged transplant survival. Limiting-dilution analysis of lymph ocytes from animals treated with hepatocytes producing only secreted alloan tigen showed an antigen-specific reduction in cytotoxic T lymphocyte (CTL) and helper T lymphocyte (HTL) precursors. Further analysis of CTL populatio ns by flow cytometry revealed a relatively high percentage of nonviable cel ls, implying that soluble antigen promotes allospecific CTL death. In summa ry, this study suggests that hepatocyte-expressed MHC class I molecules hav e opposing immunologic effects, with the membrane-bound antigen inducing im munologic sensitization, and the soluble antigen promoting donor-specific i mmunosuppression.