COMBINATION OF CYCLOSPORINE AND SPLENECTOMY SUPPRESSES INTERLEUKIN-6 PRODUCTION AND MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-II EXPRESSION AND PROLONGS CARDIAC XENOGRAFT SURVIVAL

Although untreated Lewis rat recipients will reject a transplanted ham ster heart in 3 days, accommodation of heart xenografts can be induced by treatment with cyclosporine and splenectomy, improving graft survi val to greater than 50 days. Both humoral and cellular arms of the imm une system may be involved in the mechanisms responsible for the prolo ngation of graft survival. Ou objective was to study the impact of cyc losporine 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. In bred male Lewis rats given cyclosporine 15 mg/kg per day were splenect omized 2 days after they had received heterotopic heart transplants fr om Golden Syrian hamsters. Recipients of syngeneic grafts or untreated xenografts served as controls. Plasma interleukin-6 activity was meas ured in a standard proliferation assay,vith 7TD1 hybridoma cells. Depo sition of immunoglobulin M, immunoglobulin G, and complement in heart tissue was evaluated by immunofluorescence. Cells infiltrating the gra ft that expressed major histocompatibility complex class II antigens w ere identified by immunohistochemical staining with OX6 antibodies. In xenograft recipients receiving immunosuppression, interleukin-6 activ ity, immunoglobulin M and complement deposition were significantly red uced, graft infiltration was mild, and cardiac function was good compa red with the results in those without treatment 3 and 10 days after im plantation. Inflammatory cells expressing major histocompatibility com plex class II antigens were significantly reduced in immunosuppressed xenograft recipients (2.8 +/- 0.4 cells/high power field) compared wit h those in xenogeneic controls (9.5 +/- 0.6 cells/high power field; p < 0.0005). The significant decrease in deposition of humoral component s (immunoglobulin M and complement), interleukin-6 plasma levels, and expression of major histocompatibility complex class II antigens by in flammatory cells within the nonrejecting grafts suggests that the syne rgistic benefit of cyclosporine and splenectomy depends on the attenua tion of both cellular and humoral mechanisms of xenograft rejection.