Tacrolimus (Fk506) and Sirolimus (Rapamycin) in Combination Are Not Antagonistic but Produce Extended Graft Survival in Cardiac Transplantation in the Rat1,2

Abstract

Combined use of tacrolimus (FK506) with sirolimus (rapamycin [RAPA]) was examined in a model of vascularized heart allograft in the rat. For prevention of acute rejection, three different combinations of low doses of FK506 and RAPA from day 1 up to day 14 after transplantation produced significantly longer cardiac allograft survival than each agent alone (P<0.05). Identical results were observed in a model of reversal of ongoing acute rejection, where two combinations of low doses of FK506 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 presented significantly longer heart graft survival than naive controls (P<0.05), confirming that both agents are potent immunosuppressants in the models chosen. These results also indicate that, in contrast with in vitro studies, the combined use of FK506 and RAPA in vivo did not produce antagonism, but rather had synergistic effect in prolonging the allograft survival as compared with each agent alone. It appears likely that the abundance of FKBP-12 available for binding in vivo prevents inhibitive competition of the two agents for their receptor.

Immunosuppression using the mTOR inhibition mechanism affects replacement of rat liver with transplanted cells

“…By contrast, calcineurin inhibition using Tacro or inosine monophosphate dehydrogenase inhibition using MMF did not affect the fate of transplanted cells. The combination of immunosuppressive drugs required for preventing rejection of allogeneic hepatocytes in our studies was similar to that required previously in solid organ allografts, 21 despite the differences in immune responses elicited by solid organ or cell allografts. 22 Although most current immunosuppressive drugs do not specifically target cell subsets regulating the adoptive immune system, 23,24 we found that pharmacological regulation of the innate immune system benefited transplanted cell engraftment.…”

A Comparative, Randomized Trial of Concentration-Controlled Sirolimus Combined With Reduced-Dose Tacrolimus or Standard-Dose Tacrolimus in Renal Allograft Recipients

“…The combination of sirolimus and tacrolimus is known to exhibit immunosuppressive synergy. 15 Numerous single-center reports describe sirolimus/tacrolimus-based immunosuppression in organ transplant recipients. [17][18][19][20][21][22][23][24][25] Consistent with the findings of our study, a retrospective analysis by El-Sabrout et al 19 emphasized the use of sirolimus loading doses to increase rejection-free survival.…”

“…13,14 Early preclinical experience, however, indicated that the sirolimus-tacrolimus combination exhibited immunosuppressive synergy. 15 Only a small fraction of the abundant FKBP-12 immunophilin needs to be occupied by these agents to achieve maximal immunosuppression. 16 There is an expanding body of literature on the successful clinical application of the combination of sirolimus-and tacrolimusbased immunosuppression in renal and nonerenal allograft recipients.…”

Everolimus and sirolimus antagonize tacrolimus based calcineurin inhibition via competition for FK-binding protein 12

“…Since similar FKBPs are required for successful CN inhibition by TRL and mTOR inhibition by SRL or EVL, pharmacological drug-drug interactions have been investigated by several groups. Dumont et al has shown that SRL and TRL are reciprocal antagonists [5,8], while others have demonstrated immunosuppressive synergism of these drugs [9,10].…”