Hepatic parenchymal replacement in mice by transplanted allogeneic hepatocytes is facilitated by bone marrow transplantation and mediated by CD4 cells.
The lack of adequate donor organs is a major limitation to the successful widespread use of liver transplantation for numerous human hepatic diseases. A desirable alternative therapeutic option is hepatocyte transplantation (HT), but this approach is similarly restricted by a shortage of donor cells and by immunological barriers. Therefore, in vivo expansion of tolerized transplanted cells is emerging as a novel and clinically relevant potential alternative cellular therapy. Toward this aim, in the present study we established a new mouse model that combines HT with prior bone marrow transplantation (BMT). Donor hepatocytes were derived from human alpha(1)-antitrypsin (hAAT) transgenic mice of the FVB strain. Serial serum enzyme-linked immunosorbent assays for hAAT protein were used to monitor hepatocyte engraftment and expansion. In control recipient mice lacking BMT, we observed long-term yet modest hepatocyte engraftment. In contrast, animals undergoing additional syngeneic BMT prior to HT showed a 3- to 5-fold increase in serum hAAT levels after 24 weeks. Moreover, complete liver repopulation was observed in hepatocyte-transplanted Balb/C mice that had been transplanted with allogeneic FVB-derived bone marrow. These findings were validated by a comparison of hAAT levels between donor and recipient mice and by hAAT-specific immunostaining. Taken together, these findings suggest a synergistic effect of BMT on transplanted hepatocytes for expansion and tolerance induction. Livers of repopulated animals displayed substantial mononuclear infiltrates, consisting predominantly of CD4(+) cells. Blocking the latter prior to HT abrogated proliferation of transplanted hepatocytes, and this implied an essential role played by CD4(+) cells for in vivo hepatocyte selection following allogeneic BMT.


CONCLUSIONS
The present mouse model provides a versatile platform for investigation of the mechanisms governing HT with direct relevance to the development of clinical strategies for the treatment of human hepatic failure.
Streetz
Konrad L
KL
Department of Pediatrics and Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
Doyonnas
Regis
R
Grimm
Dirk
D
Jenkins
D Denison
DD
Fuess
Sally
S
Perryman
Scott
S
Lin
Joseph
J
Trautwein
Christian
C
Shizuru
Judith
J
Blau
Helen
H
Sylvester
Karl G
KG
Kay
Mark A
MA
D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D005434:Flow Cytometry; D022781:Hepatocytes / Q000637:transplantation*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D014019:Tissue Donors; D014181:Transplantation Immunology; D023001:Transplantation Tolerance / Q000276:immunology; D014184:Transplantation, Homologous; D000515:alpha 1-Antitrypsin / Q000235:genetics
D000515:alpha 1-Antitrypsin