Role for primary immunosuppression with everolimus after pulmonary transplantation

Purpose: Everolimus is a proliferation signal inhibitor used for triple immunosuppressive therapy following solid organ transplantation. Its positive benefits, such as reduction of acute rejection episodes and reduced nephrotoxicity have been shown in kidney-as well as heart transplantation. However the role of everolimus is less well defined in lung transplantation. We thus wished to study the effect of primary immunosuppression with everolimus in a preclinical large animal lung transplantation model. Methods: Left-sided single lung transplantation from MHC-mismatched donors was performed in 11 adult minipigs. Intravenous pharmacologic immunosuppression was maintained for 28 days with 1.5 mg/kg/d methylprednisolone, 1.0 mg/kg/d azathioprine and cyclosporine A (blood levels 300-500 ng/ml; CsA group; n = 5). A further group (CsA + Ev; n = 6) received methylprednisolone, CsA (200-300 ng/ml) and Everolimus (5-10 ng/ml). Immunosuppression was discontinued on postoperative day (POD) 28. Graft survival was monitored by sequential chest X-rays, bronchoscopies and transbronchial biopsy histology. Results: All animals survived the 28 day course of immunosuppressive therapy and showed healthy grafts on POD 28. Median allograft survival in the CsA group was 55 +/- 15 days. CsA + Ev grafts showed median survival of 49 +/- 86 days (p = 0.37). Conclusion: Whereas everolimus might be advantageous as maintenance immunosuppressive agent, this data does not support an important role for everolimus in the immunosuppressive induction phase following lung transplantation.