A synergistic effect between PG490-88 and tacrolimus prolongs renal allograft survival in monkeys.
This study was undertaken to determine if PG490-88 and tacrolimus (Tac) act synergistically to prevent renal allograft rejection in monkeys and to explore possible mechanisms of synergy between these agents. MHC-mismatched renal allografts were transplanted into cynomolgus monkeys after bilateral nephrectomy. Recipients were divided into the following groups: (i) no treatment; (ii) PG490-88 (0.03 mg/kg); (iii) Tac (1 mg/kg); (iv) PG490-88 (0.01 mg/kg) + Tac (1 mg/kg) and (v) PG490-88 (0.03 mg/kg) + Tac (1 mg/kg). Through synergy PG490-88 and Tac inhibited anti-CD3/PMA-induced T-cell proliferation and IFN-gamma expression in vitro. Tac monotherapy only marginally prolonged survival (27 +/- 3.2 days), while the combination of PG490-88 and Tac significantly prolonged graft survival to a median of 99 days (PG490-88 at 0.03 mg) and 38.5 days (PG490-88 at 0.01 mg/kg). Prolonged survival correlated with inhibited IgM production as well as reduced T-cell infiltration, IL-2 protein expression and NF-AT/NF-kappaB activity. We conclude that PG490-88 and a subtherapeutic dose of Tac significantly prolong renal allograft survival in monkeys through the synergistic inhibition of T-cell activation and a decrease in IFN-gamma production and NF-AT/NF-kappaB activity.
Department of Surgery, The University of Western Ontario, London, Ontario, Canada.
G
G
Chen
H
H
Sun
J
J
Arp
B
B
Garcia
X
X
Wang
Y
Y
Wise
W
W
Liu
S
S
Ramcharran
X
X
Huang
Y
Y
Xiang
H
H
Yang
Z
Z
Fang
J
J
Madrenas
J
J
Madenas
Y
Y
Sudo
K
K
Tamura
R
R
Zhong
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D004224:Diterpenes / Q000494:pharmacology / Q000627:therapeutic use*; D004357:Drug Synergism; D006084:Graft Rejection / Q000473:pathology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects*; D000882:Haplorhini; D007075:Immunoglobulin M / Q000097:blood; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000032:analysis / Q000378:metabolism; D016030:Kidney Transplantation; D008297:Male; D016328:NF-kappa B / Q000032:analysis / Q000037:antagonists & inhibitors; D050778:NFATC Transcription Factors / Q000032:analysis / Q000037:antagonists & inhibitors; D013601:T-Lymphocytes / Q000187:drug effects; D016559:Tacrolimus / Q000494:pharmacology / Q000627:therapeutic use*; D015533:Transcriptional Activation / Q000187:drug effects
D004224:Diterpenes; D007075:Immunoglobulin M; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D007371:Interferon-gamma; C417603:omtriptolide; D016559:Tacrolimus