IN-VIVO IMMUNOGENICITY OF PURIFIED ALLOGENEIC HEPATOCYTES IN A MURINEHEPATOCYTE TRANSPLANT MODEL

Background. It has been reported previously that liver grafts and live r cells seem to be tolerogenic, based on the high frequency of spontan eous tolerance after orthotopic liver transplantation in rodents and o n the phenomenon of portal venous tolerance in other models, The purpo se of the current study was to characterize in vivo immune responses t o allogeneic hepatocytes transplanted into the portal circulation. Met hods, In this functional model of hepatocyte transplantation, ''donor' ' hepatocytes from mice transgenic for human alpha 1-antitrypsin (hA1A T) were transplanted by intrasplenic injection into host mice and the secreted hA1AT protein measured in host serum to determine hepatocellu lar graft survival, Host immune responses were assessed by measurement of donor-specific alloantibodies and delayed-type hypersensitivity re sponses. In some experiments, liver nonparenchymal cells (NPCs) were c o-transplanted with the allogeneic hepatocyte transplant. Results. All ogeneic hepatocyte transplant into immunocompetent hosts resulted in l oss of host serum hA1AT by days 7-10 after transplant, whereas syngene ic hosts maintained long-term hepatocellular graft survival as reflect ed by persistence of serum hA1AT for >20 weeks. Allogeneic hepatocyte transplantation resulted in the development of donor-specific alloanti body and delayed-type hypersensitivity responses, as well as a ''secon d set'' response of accelerated hepatocellular graft rejection after a second transplant, Pretransplantation or co transplantation of donor- matched liver NPCs at the time of allogeneic hepatocyte transplantatio n did not prolong hepatocellular allograft survival. Conclusions, Allo geneic hepatocytes introduced into the portal circulation via intraspl enic injection are immunogenic not tolerogenic and stimulate a weak hu moral and strong cell mediated host immune response in vivo. Go-transp lantation or pretransplantation of allogeneic liver NPCs did not prote ct allogeneic hepatocytes from immunologic rejection.