Co-transplantation of donor-derived hepatocytes induces long-term tolerance to cardiac allografts in a rat model.
BACKGROUND
Liver allografts transplanted between MHC-disparate mice, rats, and swine are spontaneously accepted in most strain combinations without requirement for immunosuppression. The underlying mechanism has, however, remained elusive. Here, we demonstrate that co-transplantation of donor-derived hepatocytes protect Lewis (RT1.A1) cardiac allografts from acute and chronic rejection in DA (RT1.Aa) recipients indefinitely.


METHODS
Livers of donor Lewis rats were harvested and the hepatocytes separated from hepatic leukocytes by collagenase digestion and gradient separation. DA recipient animals were transplanted Lewis cardiac allografts and simultaneously intraportally infused either Lewis-derived hepatocytes or hepatic leukocytes. Recipient animals were either not further treated or received a single dose of 15 mg/kg cyclosporine.


RESULTS
Donor hepatocytes alone significantly protected syngeneic cardiac allografts from rejection, whereas hepatic leukocytes failed to influence graft survival. In combination with cyclosporine, recipient cardiac allografts were indefinitely protected from rejection. Graft-infiltrating cells in tolerant animals presented as clusters of CD4+ T cells and stained mostly positive for interleukin-4, whereas graft-infiltrating cells in rejected allografts were predominantly positive for interferon-gamma. Adoptive transfer of splenocytes derived from tolerant animals protected Lewis cardiac allografts from rejection in DA recipients without immunosuppression. In contrast, hepatic leukocytes protected only 50% of the allografts from rejection.


CONCLUSIONS
We propose that donor hepatocytes induce permanent engraftment of syngeneic allografts by establishing a Th2 type alloresponse that is transferable to new graft recipients. The results of this study demonstrate that liver parenchymal cells significantly mediate spontaneously liver-induced tolerance.
Institute of Immunology, Department of General and Thoracic Surgery, University of Kiel, Germany.
K A
KA
Yoo-Ott
H
H
Schiller
F
F
Fändrich
H
H
Oswald
K
K
Richter
X F
XF
Xhu
W U
WU
Kampen
M
M
Krönke
N
N
Zavazava
D019264:Adoptive Transfer; D000818:Animals; D017690:Cell Transplantation; D016027:Heart Transplantation / Q000276:immunology*; D007108:Immune Tolerance; D008099:Liver / Q000166:cytology*; D051381:Rats; D011917:Rats, Inbred Lew; D013601:T-Lymphocytes / Q000276:immunology; D014184:Transplantation, Homologous