Abstract:

Current systemic immunosuppressive regimens are unable to prevent lung allograft rejection consistently and are associated with significant morbidity and death. Acute rejection has occurred in 40% and chronic rejection in 50% of our lung recipients. We hypothesized that regional immunotherapy with aerosolized cyclosporine would prevent or reduce lung allograft rejection while allowing for low systemic drug delivery. In a canine model of unilateral lung allotransplantation, aerosolized cyclosporine was delivered directly to the allograft. Acute rejection was prevented or reduced in all treated recipients. All control animals had severe acute rejection. Intragraft cyclosporine concentration was high and systemic drug delivery was low, as evidenced by low whole-blood cyclosporine levels and low tissue cyclosporine levels in skeletal muscle. Ninety-five percent of whole-blood trough cyclosporine levels were less than 150 ng/ml. Aerosolized cyclosporine was able to prevent or reduce acute pulmonary rejection and resulted in minimal systemic drug delivery.