The Role Of Regulatory T Cells In Acute Graft-verus-host Disease Following Liver Transplantation In Rats

The First PartMesenchymal stem cells administered after liver transplantation prevent acute graft-versus-host disease in ratsAim:Acute graft-versus-host disease (aGVHD) is a serious and life-threatening complication of liver transplantation (LTx), occurring in1-2%of liver allograft recipients. It is associated with considerable mortality, 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 aGVHD after LTx. Mesenchymal stem cells (MSCs) have been used to treat GVHD after allogeneic hematopoietic stem cell transplantation and shown to induce Tregs, which have immunomodulatory effects.Methods and materials:In this study, rats after LTx were treated with MSCs of different origins and dosages from day0to day+6after LTx. Regulatory T cells were tested by flow cytometry and immunohistochemistry. MSCs co-cultured with mixed lymphocyte reaction (MLR) to test their function on regulatory T cells. Results:Rats that received MSCs of either donor or recipient origin survived significantly longer than the control group, and surviving MSC treated rats did not show typical LTx-aGVHD symptoms. Flow cytometry analysis showed that the ratios of Tregs in peripheral blood were more abundant in the MSC groups than in the control group. More immunohistochemically stained Foxp3+cells in the intestine was also found in the MSC groups than in the control group. Further investigations into the function of MSCs showed that they could increase the ratio of Tregs in MLR and lead to a greater reduction in MLR proliferation in vitro.Conclusion:Administration of MSCs of either donor or recipient origin after LTx in our rat model could prevent the onset of LTx-aGVHD.The Second PartEffects of trichostatin A in a rat model of acute graft-versus-host disease following liver transplantationAim:Acute graft-versus-host disease (aGVHD) is a rare but serious and life-threatening complication of liver transplantation (LTx). Previously, we have demonstrated that the development of aGVHD following liver transplantation (LTx-aGVHD) is associated with a decreased percentage of regulatory T cells (Tregs) in the peripheral blood of recipients. Histone deacetylase inhibitors (HDACi) promote the production of Tregs and some, such as suberoylanilide hydroxamic acid (SAHA) and trichostatin A (TSA), are used to treat autoimmune diseases, including GVHD following bone marrow transplantation.Methods and materials:In this study, LTx-aGVHD rats were treated with TSA continuously for7days from day8to day14after LTx. Subsequently, splenic T cells were used for in vitro investigations of the mechanism of action of Tx.Results:All LTx-aGVHD rats developed typical LTx-aGVHD symptoms following TSA treatment and died from LTx-aGVHD. The percentage frequency of Tregs in PBMCs was slightly upregulated after TSA treatment, while TSA dramatically downregulated Foxp3protein and mRNA levels both in vivo and in vitro. Furthermore, TSA impaired T cell proliferation and production of pro-and anti-inflammatory cytokines in vitro.Conclusion:TSA does not abrogate LTx-aGVHD in rats due to downregulation of Tregs.