TACROLIMUS (FK506) AND SIROLIMUS (RAPAMYCIN) IN COMBINATION ARE NOT ANTAGONISTIC BUT PRODUCE EXTENDED GRAFT-SURVIVAL IN CARDIAC TRANSPLANTATION IN THE RAT

Combined use of tacrolimus (FK506) with sirolimus (rapamycin [RAPA]) w as examined in a model of vascularized heart allograft in the rat. For prevention of acute rejection, three different combinations of low do ses of FK506 and RAPA from day 1 up to day 14 after transplantation pr oduced significantly longer cardiac allograft survival than each agent alone (P<0.05). Identical results were observed in a model of reversa l of ongoing acute rejection, where two combinations of low doses of F K506 and RAPA from day 4 up to day 18 after surgery also demonstrated significantly longer graft survival than each immunosuppressant alone (P<0.05). All the low-dose-treated groups in these two models presente d significantly longer heart graft survival than naive controls (P<0.0 5), confirming that both agents are potent immunosuppressants in the m odels chosen. These results also indicate that, in contrast with in vi tro studies, the combined use of FK506 and RAPA in vivo did not produc e antagonism, but rather had synergistic effect in prolonging the allo graft survival as compared with each agent alone. It appears likely th at the abundance of FKBP-12 available for binding in vivo prevents inh ibitive competition of the two agents for their receptor.