Sirolimus (rapamycin) potentiates cyclosporine in prevention of acute lungrejection

Background: Cyclosporine-based immunosuppressive regimens (INN: ciclosporin ) in human lung transplantation continue to result in a high incidence of a cute cellular rejection. We investigated the use of sirolimus, a macrolide with structural similarity to tacrolimus, as monotherapy and in combination with cyclosporine in a rodent lung transplant model. Methods: Orthotopic l eft lung transplantation was performed in Lewis recipients from Brown-Norwa y donor rats with syngeneic Lewis-to-Lewis controls. Open biopsies were per formed on postoperative day 7, and the severity of acute lung rejection was graded by a pathologist blinded to the protocol. Results: All recipients s urvived despite the amount of acute rejection seen on examination of the bi opsy tissue. Lewis-to-Lewis isografts demonstrated near normal pulmonary ar chitecture, Allogeneic recipients receiving high-dose cyclosporine (25 mg/k g) monotherapy showed mild to moderate acute rejection with some perivascul ar focal interstitial infiltrates, Recipients receiving low-dose cyclospori ne (5 mg/kg) monotherapy or low- or high-dose sirolimus (0.5 or 2.0 mg/kg, respectively) monotherapy demonstrated massive cellular infiltration leadin g to necrosis and infarction and could not be graded. However, the addition of low-dose sirolimus (0.5 mg/kg) to low-dose cyclosporine (5 mg/kg) demon strated a significant potentiating immunosuppressive effect, and the additi on of high-dose sirolimus (2.0 mg/kg) to low-dose cyclosporine (5.0 mg/kg) demonstrated an even greater effect, with rejection scores better than thos e obtained with high-dose cyclosporine monotherapy and similar to those obt ained with isografts, Conclusions: This study demonstrates that low-dose si rolimus has a cyclosporine-sparing effect and that a higher dose of sirolim us in combination with cyclosporine strongly protects lung allografts from acute cellular rejection. These results suggest that sirolimus may be indic ated as an adjunct to current cyclosporine-based immunosuppressive regimens in clinical lung transplantation.