OSI-027 modulates acute graft-versus-host disease after liver transplantation in a rat model

Despite its rarity (1%–2%), acute graft-versus-host disease after liver transplantation (LTx-aGVHD) has a high mortality rate (85%). A gradual decrease in regulatory T cells (T-regs) correlates with disease progression in a rat LTx-GVHD model and treatments which increase T-regs exert therapeutic effects on LTx-aGVHD. In this study, LTx-aGVHD model rats were treated with rapamycin (RAPA), OSI-027 or an equal quantity of vehicle. Rats treated with OSI-027 survived longer (>100 days) than those in the RAPA (70±8 days) or control (24±3 days) groups. Flow cytometric analysis showed that the T-reg ratios in peripheral blood mononuclear cells in the OSI-027 group were higher than those in the RAPA or control groups. The proportions of donor-derived lymphocytes in the OSI-027 group were lower than those in the RAPA or control groups. Hematoxylin and eosin staining of skin tissue demonstrated less severe lymphocyte infiltration in the OSI-027 group than that in the RAPA or control groups. In vitro, OSI-027 induced differentiation of CD4+CD25- T cells into CD4+CD25+Foxp3+ T-regs. Furthermore, injection of OSI-027-induced donor-derived CD4+CD25+ T cells into the peripheral blood of LTx-aGVHD model rats prevented LTx-aGVHD. Thus, OSI-027 is implicated as a novel method for the treatment of LTx-aGVHD. This article is protected by copyright. All rights reserved.