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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.