A Synergistic Effect Between PG490-88 and Tacrolimus Prolongs Renal Allograft Survival in Monkeys

Authors

G. Chen, The University of Western OntarioFollow
H. Sun, The University of Western OntarioFollow
J. Arp, The University of Western OntarioFollow
B. Garcia, The University of Western OntarioFollow
X. Wang, The University of Western Ontario
Y. Wise, The University of Western Ontario
W. Liu, The University of Western OntarioFollow
S. Ramcharran, The University of Western Ontario
X. Huang, The University of Western Ontario
Y. Xiang, The University of Western OntarioFollow
H. Yang, The University of Western Ontario
Z. Fang, The University of Western Ontario
J. Madrenas, Robarts Research Institute, The University of Western OntarioFollow
Y. Sudo, Fujisawa Pharmaceutical Co. Ltd., Osaka, Japan
K. Tamura, Fujisawa Pharmaceutical Co. Ltd., Osaka, Japan
R. Zhong, The University of Western Ontario

Document Type

Article

Publication Date

4-2006

Journal

American Journal of Transplantation

Volume

6

Issue

4

First Page

714

Last Page

723

URL with Digital Object Identifier

http://dx.doi.org/10.1111/j.1600-6143.2006.01257.x

Abstract

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.