In vivo immunogenicity of purified allogeneic hepatocytes in a murine hepatocyte transplant model.
BACKGROUND
It has been reported previously that liver grafts and liver cells seem to be tolerogenic, based on the high frequency of spontaneous tolerance after orthotopic liver transplantation in rodents and on the phenomenon of portal venous tolerance in other models. The purpose of the current study was to characterize in vivo immune responses to allogeneic hepatocytes transplanted into the portal circulation.


METHODS
In this functional model of hepatocyte transplantation, "donor" hepatocytes from mice transgenic for human alpha1-antitrypsin (hA1AT) were transplanted by intrasplenic injection into host mice and the secreted hA1AT protein measured in host serum to determine hepatocellular graft survival. Host immune responses were assessed by measurement of donor-specific alloantibodies and delayed-type hypersensitivity responses. In some experiments, liver nonparenchymal cells (NPCs) were co-transplanted with the allogeneic hepatocyte transplant.


RESULTS
Allogeneic hepatocyte transplant into immunocompetent hosts resulted in loss of host serum hA1AT by days 7-10 after transplant, whereas syngeneic hosts maintained long-term hepatocellular graft survival as reflected by persistence of serum hA1AT for > 20 weeks. Allogeneic hepatocyte transplantation resulted in the development of donor-specific alloantibody and delayed-type hypersensitivity responses, as well as a "second 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 transplantation did not prolong hepatocellular allograft survival.


CONCLUSIONS
Allogeneic hepatocytes introduced into the portal circulation via intrasplenic injection are immunogenic not tolerogenic and stimulate a weak humoral and strong cell mediated host immune response in vivo. Co-transplantation or pretransplantation of allogeneic liver NPCs did not protect allogeneic hepatocytes from immunologic rejection.
Bumgardner
G L
GL
Department of Surgery, Ohio State University, Columbus 43210, USA.
Li
J
J
Heininger
M
M
Ferguson
R M
RM
Orosz
C G
CG
D000818:Animals; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006085:Graft Survival; D006801:Humans; D006968:Hypersensitivity, Delayed; D007111:Immunity, Cellular; D007518:Isoantibodies / Q000096:biosynthesis; D008099:Liver / Q000276:immunology*; D016031:Liver Transplantation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000515:alpha 1-Antitrypsin / Q000235:genetics
D007518:Isoantibodies; D000515:alpha 1-Antitrypsin