Prevention of graft-versus-host disease by a novel immunosuppressant, (5R)-5-hydroxytriptolide (LLDT-8), through expansion of regulatory T cells

Abstract

(5R)-5-hydroxytriptolide (LLDT-8) is a new compound derived from triptolide, which is the major immunosuppressive fraction of Tripterygium wilfordii Hook. F (TWHF). In this study, we demonstrated that administration of LLDT-8 (1 mg/kg/day, p.o.) effectively prevented weight loss and death induced by allo-BMT (BLAB/c, H-2 d to C57BL/6, H-2 b), and extended survival in allo-BMT model of aGVHD. Following days 7 to 28 after allo-BMT, the allogeneic graft survived by increasing the number of engrafted cells (H-2 d) in spleens of recipient mice with LLDT-8 treatment. To construe the immunosuppressive effects of LLDT-8, the splenocytes (H-2 d) of LLDT-8 treated recipients (H-2 b) were tested for the proliferative responses to donor antigen (H-2 d), host antigen (H-2 b) and mitogen (ConA) stimulations, respectively, the results indicated that LLDT-8 induced the T cells' unresponsiveness to donor and host antigens, while still maintaining response to ConA; Compared with the vehicle group of GVHD mice, administration of LLDT-8 significantly inhibited T cells to produce IFN-γ with or without host antigen or ConA stimulation. Further studies indicated LLDT-8 had a normalizing effect on the ratio of CD4 + / CD8 + T cells, and increased CD4 +CD25 + T regulatory cells with the Foxp3 expression in splenocytes from LLDT-8 treated mice. The results outline the great potential of LLDT-8 as a therapeutic tool to induce suppression in GVHD.