Notch signal pathway inhibitor alleviates acute graft-versus-host-disease after allogeneic bone marrow transplantation in murine model

Abstract

Objective To investigate the effects and mechanism of Notch signal pathway inhibitor (γ-secretase inhibitor, GSI) on acute graft versus host disease (aGVHD) after allogeneic bone marrow transplantation (allo-BMT). Method The recipients were BABL/c mice, while the donors were C57BL/6 mice. The murine model of aGVHD had been established by allo-BMT with donor-derived T cells. Experiment was divided into 6 groups: control group (C), radiation control group (R), transplantation group (B+ S), transplantation control group (B+ S+ D), GSI-1 treated group and GSI-2 treated group. Mice in GSI-1 treated group were daily intraperitoneally injected with GSI (5 mol/kg) (at day 1 before transplantation and day 1, 3 after transplantation). Mice in GSI-2 treated group were daily intraperitoneally injected wtih GSI (5 mol/kg) (at day 1, 2, 3 after transplantation). Result The results showed that the incidence of aGVHD in GSI-1 and GSI-2 treated groups was 60% and 50% respectively, significantly lower than that in transplantation control group (B+ S+ D) (90%) (P<0.01). The survival time in GSI-1 and GSI-2 treated groups was 25.40±3.13 and 25.20±3.43 days respectively, significantly longer than that in transplantation control group (17.40±2.32 days) (P<0.01), and the aGVHD pathological changes in GSI-1 and GSI-2 treated groups were milder than those in transplantation control group. At 7th day after transplantation, the IL-4 levels in GSI-1 and GSI-2 treated groups were 31.71±1.60 and 29.27±1.86 ng/L, significantly higher than those in transplantation control group (23.04±1.82 ng/L) (P<0.01, and P<0.05 respectively). The IFN-γ levels in GSI-1 and GSI-2 treated groups were 25.97±1.15 and 22.69±3.01 ng/L respectively, significantly lower than those in transplantation control group (36.77±2.62 ng/L) (P<0.01). Conclusion It is concluded that GSI may alleviate or suppress lethal aGVHD, and elevate the survival rate after allo-BMT in murine model. Accommodation of the Th1 and Th2 cytokine levels is the possible mechanism of GSI preventing lethal aGVHD. Key words: Mice; Bone marrow transplantation; Graft-versus-host-disease; Notch signal pathway; Cytokine