Suppression of (5R)-5-hydroxytriptolide (LLDT-8) on allograft rejection in full MHC-mismatched mouse cardiac transplantation.
BACKGROUND
(5R)-5-hydroxytriptolide (LLDT-8) is a new compound derived from triptolide, which is the major immunosuppressive fraction of Tripterygium wilfordii Hook. F (TWHF). Studies in vitro and in vivo have demonstrated that LLDT-8 had potent immunosuppressive activities. Here we tested LLDT-8 in major histocompatibility complex (MHC)-mismatched cardiac transplantation and investigated the mechanisms underlying the prevention of transplant rejection.


METHODS
LLDT-8 was administered orally to recipients in Balb/c to C57BL/6 murine cardiac transplantation model. Allograft survival after transplantation was recorded in recipients. The T cell immunity and cytokine production were observed. Histological analysis was performed. The chemokine and its receptor were analyzed by reverse transcriptase-polymerase chain reaction on cardiac graft RNA.


RESULTS
LLDT-8 administered orally significantly induced the survival prolongation of allogeneic cardiac graft. Histological results showed that LLDT-8 well preserved myocardium and significantly reduced infiltration of the graft with inflammatory cells. LLDT-8 decreased IL-2 production in recipient splenocytes stimulated by concanavalin A (ConA) ex vivo. LLDT-8 significantly inhibited the immunoreactivity of recipient to specific donor alloantigens, but preserved immunity to third-party alloantigens and mitogen. However, the flow cytometry analysis of the proportion of CD4+, CD8+ T cell subgroup in recipient spleens showed LLDT-8 had a normalizing effect on the splenic lymphocytes population. LLDT-8 decreased CC chemokine receptor 5 (CCR5) and their ligands macrophage inflammatory protein 1 alpha (MIP-1alpha) and beta (MIP-1beta) mRNA expressions in allografts.


CONCLUSIONS
The results outline the great potential of LLDT-8 as a therapeutic tool in transplant rejection.
Laboratory of Immunopharmacology, State Key Laboratory of Drug Research, Shanghai Institutes of Materia Medica and Biological Sciences, Graduate School of the Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, P.R. China.
Wei
W
Tang
Ru
R
Zhou
Yang
Y
Yang
Yuan-chao
YC
Li
Yi-fu
YF
Yang
Jian-ping
JP
Zuo
D000818:Animals; D004224:Diterpenes / Q000627:therapeutic use*; D006084:Graft Rejection / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects; D016027:Heart Transplantation / Q000276:immunology; D006650:Histocompatibility Testing; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007376:Interleukin-2 / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D019713:Receptors, CCR5 / Q000032:analysis; D016176:T-Lymphocyte Subsets / Q000187:drug effects; D014184:Transplantation, Homologous
C509074:5-hydroxytriptolide; D004224:Diterpenes; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D019713:Receptors, CCR5