Sirolimus-mediated prolongation of rat cardiac allograft survival is enhanced by beta1 integrin very late antigen-4 blockade.
The beta1 integrin very late antigen-4 (VLA-4) plays a key role in lymphocyte rolling and adhesion to endothelium, and in lymphocyte migration through fibronectin. Thus, VLA-4 blockade may modulate allograft rejection. Here, we examined the effect of WAY-279, a small molecule VLA-4 antagonist, combined with sirolimus in a model of vascularized heart allograft (BN --> LEW) in the rat. Recipients were treated with low doses of WAY-279 (10-50 mg/kg, bid) and/or sirolimus (0.04 mg/kg) for 14 days, starting on the day of transplantation. The median-effect principle and the combination index (CI) were used to assess the combined effect of WAY-279 and sirolimus (CI < 1: synergism; CI = 1: summation; CI > 1 antagonism). Low doses of WAY-279 or sirolimus alone slightly prolonged allograft survival as compared to control group (MST = 7 days). When recipients were treated with WAY-279 and sirolimus, the cardiac allograft survival was synergistically prolonged for up to 45 days (P < .001; CI = 0.174-0.970). We showed that a concomitant treatment of WAY-279 with sirolimus produced a synergistic effect in prolonging cardiac allograft survival in the rat.
Vu
M D
MD
Laboratory of Experimental Surgery, Research Center of CHUM, Notre-Dame Hospital, University of Montreal, Quebec, Canada.
Qi
S
S
Sehgal
S N
SN
Chen
H
H
Kennedy
J D
JD
D000818:Animals; D006085:Graft Survival / Q000187:drug effects*; D016027:Heart Transplantation / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors*; D019012:Integrin beta1 / Q000276:immunology; D023421:Models, Animal; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D020123:Sirolimus / Q000494:pharmacology*
D007166:Immunosuppressive Agents; D039041:Integrin alpha4beta1; D019012:Integrin beta1; D020123:Sirolimus