Rapamycin and tacrolimus differentially modulate acute graft-versus-host disease in rats after liver transplantation

Abstract

Acute graft-versus-host disease (aGVHD) is a serious complication of liver transplantation (LTx); it occurs in 1% to 2% of liver allograft recipients. The condition has a poor prognosis and poses major diagnostic and therapeutic challenges. A rat model of aGVHD after LTx has been developed, and a relative decrease in regulatory T (Treg) cells has been shown to be associated with this model. Interest has been expressed in the effects of different immunosuppressive agents on CD4+CD25+Foxp3+ Treg cell homeostasis. Rats with aGVHD after LTx were treated with tacrolimus (FK506), rapamycin (RAPA), or no immunosuppressive drug. Those that received RAPA survived longer (91.4 ± 8.1 days) than those in the FK506 group (62.3 ± 13.4 days) or the control group (22.9 ± 1.2 days). Flow cytometry analysis showed that Treg cells, as a percentage of peripheral blood mononuclear cells (PBMCs), were more abundant in the RAPA group (6.8% ± 0.8%) than in the FK506 group (1.7% ± 0.4%) or the control group (2.0% ± 0.4%). Immunohistochemistry demonstrated more Foxp3+ staining of intestinal cells in the RAPA group than in the FK506 group or the control group. In conclusion, the reduced mortality induced by RAPA in a rat model of aGVHD after LTx was associated with higher percentages of CD4+CD25+Foxp3+ Treg cells in PBMCs in blood and tissues than those occurring after the administration of FK506. © 2009 AASLD.