Mesenchymal stem cells administered after liver transplantation prevent acute graft-versus-host disease in rats

Acute graft-versus-host disease is a serious and life-threatening complication of liver transplantation (LT) that occurs in 1% to 2% of liver allograft recipients. It is associated with a high mortality rate, and effective therapies are lacking. In our established rat model, a relative decrease in regulatory T cells (Tregs) was previously shown to be associated with acute graft-versus-host disease after liver transplantation (LT-aGVHD). Mesenchymal stem cells (MSCs) have been used to treat graft-versus-host disease after allogeneic hematopoietic stem cell transplantation, and they have been shown to induce Tregs, which have immunomodulatory effects. In this study, when a treatment with donor- or recipient-derived MSCs was administered from day 8 to day 14 after the typical symptoms of LT-aGVHD started, the recipients were not cured, and their survival time was not prolonged. However, when MSCs of different origins were administered from day 0 to day 6 after LT, the recipients survived significantly longer than the control group, and the surviving MSC-treated rats did not show typical LT-aGVHD symptoms. In vivo tracings of carboxyfluorescein diacetate succinimidyl esterstained MSCs did not show significant accumulations in the target organs after administration. Flow cytometry analysis showed that the Treg ratios in peripheral blood were more higher for the MSC-treated groups versus the control group. More immunohistochemically stained forkhead box P3positive cells were also found in the intestines of the MSC-treated groups versus the control group. Further investigations of the function of MSCs showed that they could increase the Treg ratio in a mixed lymphocyte reaction (MLR) and lead to a greater reduction in MLR proliferation in vitro. In conclusion, the post-LT administration of MSCs of either donor or recipient origin could prevent the onset of LT-aGVHD in our rat model. Liver Transpl 18:696706, 2012. (C) 2012 AASLD.