Analysis of cellular events in hepatic allografts: donor progenitors induce intragraft chimerism

Long-term graft acceptance and tolerance induction after allogeneic rat liver transplantation are well described. However, the underlying mechanisms remain unclear. In this study we investigated the cellular events within the liver graft during initial immunosuppression and long-term acceptance. Orthotopic liver transplantation was performed in the Dark Agouti (DA)-to-Lewis (LEW) and LEW-to-DA rat strain combination. In order to achieve long-term acceptance, LEW recipients of DA livers were treated with two different short-term therapies. Non-parenchymal cells (NPC) were isolated from liver allografts on days + 10 and + 100 after transplantation and donor-specific leukocytes were immunophenotyped by flow cytometry. Both the monotherapy and triple therapy prolonged graft survival (> 100 days). Liver allografts from LEW donors into DA recipients were spontaneously accepted across a complete MHC mismatch without immunosuppression. Liver allograft rejection was induced by infiltrating alloreactive immunocompetent cells. But the intensities of cell infiltration in the early and late phases after transplantation did not correlate with eventual outcome. Donor-specific NPC decreased to 18-25% on day + 10 in both therapeutic groups, but had rebounded to up to 40% by day + 100. Recurrence of donor-specific cells was caused almost exclusively by rising T cell counts. The persistence of dendritic cells in the late phase after transplantation could be clearly demonstrated. Repopulation by donor-specific T lymphocytes was observed in long-term accepted liver grafts. This recurrence may be based on the differentiation of liver-derived progenitor cells. The persistent coexistence of donor and recipient cells within the liver allograft (intrahepatic chimerism) appears to be characteristic and may be important for long-term acceptance.