Sirolimus-mediated prolongation of rat cardiac allograft survival is enhanced by beta1 integrin very late antigen-4 blockade.

ABSTRACT

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.