The Role Of OSI-027 In Modulates Acute Graft-versus-host Disease After Liver Transplantationin A Rat Model

The First PartmTOR inhibitor OSI-027 modulates acutegraft-versus-hostdisease after liver transplantation in a rat modelObjectiveAlthough acute graft-versus-host disease (aGVHD) is an uncommon (1%-2%) complication of liver transplantation (LT), the high mortality (85%-90%) poses a major therapeutic challenge. The precise mechanisms of it remain to be elucidated, and the effective methods for therapy are lacking. Our previous studies found that the relative decrease in the proportion of regulatory T cells (T-regs) in the peripheral blood mononuclear cells (PBMCs) is associated with disease progression. Rapamycin (RAPA) increaseing the percentage of T-regs in the PBMCs can improve the survival rate of LTx-aGVHD rats. In this study we compared the effects of OSI-027 and RAPA as immune inhibitors in the treatment of LTx-aGVHD in a rat model.Materials and methodsLTx-aGVHD model rats were treated with rapamycin (RAPA), OSI-027 or an equal quantity of vehicle from the 7 to 14 days after liver transplantation. The rates of regular T cells (T-regs), the infiltration of mononuclear cells in skin tissue and the inflammatory cytokines were detected.ResultsOSI-027 was more effective than RAPA in raising the rates of T-regs and in reducing inflammatory cytokines and the infiltration of mononuclear cells in skin tissue. The rats in OSI-027 group were healthier and survival longer than that in RAPA group.ConclusionsOSI-027 was more effective than RAPA in treating rat LTx-aGVHD.The Second PartThe mechanism of OSI-027 in modulates acute graft-versus-hostdisease after liver transplantation in a rat modelObjectiveAcute graft-versus-host disease after liver transplantation (LTx-aGVHD) is a lethal complication and the precise mechanisms of it remained unclear. Our previous studies found that the relative decrease in the proportion of regulatory T cells (T-regs) in the peripheral blood mononuclear cells (PBMCs) is associated with disease progression. The new mTOR inhibitor OSI-027 was more effective than RAPA in raising the rates of T-regs and prolonging the survival time. In this study, we aimed to reveal the mechanisms of OSI-027 in treating LTx-aGVHD.Materials and methodsLTx-aGVHD model rats were treated with rapamycin (RAPA), OSI-027 or an equal quantity of vehicle from the 7 to 14 days after liver transplantation. The rates of regular T cells (T-regs) and the expression of mTOR pathway effectors were detected. In vitro mixed lymphocyte culture, the functions of mTOR in regulating T-regs were explored. We also induced T-regs in vitro and injected them into LTx-aGVHD rats to exam the role of T-regs in treating LTx-aGVHD.ResultsIn OSI-027 group, most of the T-regs were donor-derived. OSI-027 was more potent than RAPA in inhibiting mTORCl/mTORC2 and promoting the differentiation of CD4+CD25-T cells into T-regs. OSI-027 induced T-regs could prevent the occurrence of LTx-aGVHD.ConclusionsOSI-027 could modulate LTx-aGVHD through suppressing mTORCl/mTORC2 and promote CD4+CD25-T cell differentiating into T-regs.