Prevention of graft-versus-host disease by a novel immunosuppressant, (5R)-5-hydroxytriptolide (LLDT-8), through expansion of regulatory T cells.
(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-2d to C57BL/6, H-2b), 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-2d) in spleens of recipient mice with LLDT-8 treatment. To construe the immunosuppressive effects of LLDT-8, the splenocytes (H-2d) of LLDT-8 treated recipients (H-2b) were tested for the proliferative responses to donor antigen (H-2d), host antigen (H-2b) 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-gamma 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.
Tang
Wei
W
Laboratory of Immunopharmacology, Graduate School of the Chinese Academy of Sciences, State key laboratory of drug research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.
Yang
Yang
Y
Zhang
Fan
F
Li
Yuan-Chao
YC
Zhou
Ru
R
Wang
Jun-xia
JX
Zhu
Yi-na
YN
Li
Xiao-yu
XY
Yang
Yi-fu
YF
Zuo
Jian-ping
JP
D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D016026:Bone Marrow Transplantation; D016516:CD4-CD8 Ratio; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004224:Diterpenes / Q000008:administration & dosage / Q000494:pharmacology*; D006085:Graft Survival / Q000187:drug effects; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control*; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017710:Lymphocyte Transfusion; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology
C509074:5-hydroxytriptolide; D015703:Antigens, CD; D004224:Diterpenes; D007166:Immunosuppressive Agents; D012333:RNA, Messenger