A FUNCTIONAL-MODEL OF HEPATOCYTE TRANSPLANTATION FOR IN-VIVO IMMUNOLOGICAL STUDIES

Background. Previous studies to determine the significant donor and ho st factors which contribute to immune responses to allogeneic hepatocy tes have been pursued with in vitro and in vivo studies. However, in o rder to further characterize in vivo host immune responses to transpla nted hepatocytes in conjunction with their consequences upon allograft survival, a functional model of hepatocyte transplantation in which t he function and survival of transplanted hepatocytes could be serially assessed was pursued, Methods. A transgenic mouse line expressing the human alpha(1)-antitrypsin (hA1AT) gene was developed in an FVB/N (H2 (q)) mouse (hA1AT-FVB/N), Hepatocytes from these ''donor'' transgenic mice were transplanted into host mice by intrasplenic injection, and s ubsequent survival of the transgenic hepatocytes was determined by ass ay for the secreted hA1AT protein in host serum by enzyme-linked immun osorbent assay, Results. Transplantation of transgenic ''donor'' hepat ocytes (hA1AT-FVB/N) into (a) syngeneic FVB/N (H2(q)), (b) allogeneic immunoincompetent C57BL/6.SCID (H2(b)), or (c) allogeneic T cell-defic ient (outbred) hosts resulted in long-term survival (>16 weeks) of hep atocytes. Transplantation of allogeneic hepatocytes (hA1AT-FVB/N, H2(q )) into C57BL/6 (H2(b)), C3H (H2(k)), or BALB/c (H2(d)) hosts resulted in loss of hA1AT in host serum by day 10 after transplant. Likewise, transplantation of allogeneic hepatocytes into hosts deficient in B ce lls, CD8(+) T cells, or CD4(+) T cells resulted in loss of hA1AT by da y 10 after transplant, Conclusions. This functional model of hepatocyt e transplantation is validated for the study of host immune responses to hepatocellular grafts and to assess efficacy of strategies designed to alter these in vivo immune responses, The immunologic rejection of allogeneic hepatocytes appears to be T cell-mediated.