Immunosuppression with a combination of pg490-88 and a subtherapeutic dose of FK506 in a canine renal allograft model.
BACKGROUND
PG490-88 is a water soluble, semisynthetic derivative of a novel compound PG490 (triptolide) purified from the Chinese herb Tripterygium Wilfordii Hook F. In this study, we evaluated the immunosuppressive effect of PG490-88 alone or combined with FK506 in a dog renal transplantation model.


METHODS
Recipient and donor male beagle dogs were obtained from different breeders to ensure MHC mismatching. PG490-88 and/or FK506 were administered orally based on protocol design.


RESULTS
All dogs in the untreated group developed acute vascular rejection with a median survival time of 6 days. The grafts from this group presented with massive hemorrhage, IgM, IgG, and C4c deposition. Administration of PG490-88 0.06 mg/kg/day significantly prolonged graft survival to a median survival time of 11 days (P=0.038, vs. control). Treatment with FK506 0.3 mg/kg/day did not prolong graft survival with a median survival time of 9 days. Although FK506 0.6 mg/kg/day significantly prolonged survival, this dose was not tolerated by the dogs. The combination of PG 0.06 mg/kg/day and FK506 0.3 mg/kg/day significantly prolonged survival to a median survival time of 15 days (P=0.017, vs. control). Compared to the untreated control group, the pattern of acute humoral rejection was attenuated in renal allografts treated with PG490-88 and/or FK506. C4c deposition was significantly decreased in renal allografts treated with PG490-88 monotherapy and combination therapy.


CONCLUSIONS
PG490-88 alone and combined with low dose FK506 significantly prolonged renal allograft survival in a dog model. This agent attenuated acute humoral rejection by inhibiting complement activation and T-cell infiltration.
Wang
Ximo
X
Department of Surgery, The University of Western Ontario, London, Ontario N6A 5A5, Canada.
Sun
Hongtao
H
Chen
Gang
G
Liu
Weihua
W
Wise
Yishai
Y
Yung
Chenlin
C
Sudo
Yuji
Y
Tamura
Kouichi
K
Garcia
Bertha
B
Zhong
Robert
R
D000818:Animals; D003404:Creatinine / Q000097:blood; D004224:Diterpenes / Q000627:therapeutic use*; D004285:Dogs; D004359:Drug Therapy, Combination; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D016030:Kidney Transplantation / Q000276:immunology*; D008991:Monitoring, Physiologic / Q000379:methods; D016019:Survival Analysis; D016559:Tacrolimus / Q000627:therapeutic use*; D013997:Time Factors; D014184:Transplantation, Homologous / Q000276:immunology; D017329:Triptorelin Pamoate / Q000627:therapeutic use
D004224:Diterpenes; D007166:Immunosuppressive Agents; D017329:Triptorelin Pamoate; D003404:Creatinine; C417603:omtriptolide; D016559:Tacrolimus