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 r equirement for immunosuppression. The underlying mechanism has, however, re mained elusive. Here, we demonstrate that co-transplantation of donor-deriv ed hepatocytes protect Lewis (RT1.A(1)) cardiac allografts from acute and c hronic rejection in DA (RT1.A(a)) recipients indefinitely. Methods. Livers of donor Lewis rats were harvested and the hepatocytes sepa rated from hepatic leukocytes by collagenase digestion and gradient separat ion. DA recipient animals were transplanted Lewis cardiac allografts and si multaneously intraportally infused either Lewis-derived hepatocytes or hepa tic leukocytes, Recipient animals were either not further treated or receiv ed a single dosis of 15 mg/kg cyclosporine. Results. Donor hepatocytes alone significantly protected syngeneic cardiac allografts from rejection, whereas hepatic leukocytes failed to influence g raft survival. In combination with cyclosporine, recipient cardiac allograf ts 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 a llografts were predominantly positive for interferon-gamma, Adoptive transf er of splenocytes derived from tolerant animals protected Lewis cardiac all ografts from rejection in DA recipients without immunosuppression. In contr ast, hepatic leukocytes protected only 50% of the allografts from rejection . Conclusion. We propose that donor hepatocytes induce permanent engraftment of syngeneic allografts by establishing a Th2 type alloresponse that is tra nsferable to new graft recipients. The results of this study demonstrate th at liver parenchymal cells significantly mediate spontaneously liver-induce d tolerance.