Combination of cyclosporine and splenectomy suppresses interleukin-6 production and major histocompatibility complex class II expression and prolongs cardiac xenograft survival.

Abstract

Although untreated Lewis rat recipients will reject a transplanted hamster heart in 3 days, accommodation of heart xenografts can be induced by treatment with cyclosporine and splenectomy, improving graft survival to greater than 50 days. Both humoral and cellular arms of the immune system may be involved in the mechanisms responsible for the prolongation of graft survival. Our objective was to study the impact of cyclosporine and splenectomy on the deposition of antibodies, complement, or both within the graft. We also compared the cellular component of inflammation in treated recipients with that in untreated controls. Inbred male Lewis rats given cyclosporine 15 mg/kg per day were splenectomized 2 days after they had received heterotopic heart transplants from Golden Syrian hamsters. Recipients of syngeneic grafts or untreated xenografts served as controls. Plasma interleukin-6 activity was measured in a standard proliferation assay with 7TD1 hybridoma cells. Deposition of immunoglobulin M, immunoglobulin G, and complement in heart tissue was evaluated by immunofluorescence. Cells infiltrating the graft that expressed major histocompatibility complex class II antigens were identified by immunohistochemical staining with OX6 antibodies. In xenograft recipients receiving immunosuppression, interleukin-6 activity, immunoglobulin M and complement deposition were significantly reduced, graft infiltration was mild, and cardiac function was good compared with the results in those without treatment 3 and 10 days after implantation. Inflammatory cells expressing major histocompatibility complex class II antigens were significantly reduced in immunosuppressed xenograft recipients (2.8 +/- 0.4 cells/high power field) compared with those in xenogeneic controls (9.5 +/- 0.6 cells/high power field; p < 0.0005). The significant decrease in deposition of humoral components (immunoglobulin M and complement), interleukin-6 plasma levels, and expression of major histocompatibility complex class II antigens by inflammatory cells within the nonrejecting grafts suggests that the synergistic benefit of cyclosporine and splenectomy depends on the attenuation of both cellular and humoral mechanisms of xenograft rejection.