Triple immunosuppression reduces mononuclear cell infiltration and prolongs graft life in pig-to-newborn baboon cardiac xenotransplantation

OBJECTIVE: Pig hearts transplanted into unmedicated newborn baboons do not undergo hyperacute rejection by preformed xenoantibody and complement. These grafts are rejected at days 3 to 4 in association with the infiltration of macrophages and natural killer cells. We investigated whether an immunosuppressive regimen used widely in cardiac allotransplantation could reduce this cellular response and prolong xenograft life. METHODS: Ten newborn baboons underwent heterotopic pig cardiac xenotransplantation. Five baboons were immunosuppressed with mycophenolate mofetil (100 mg/kg), methylprednisolone acetate (0.8 mg/kg), and cyclosporine A (INN: ciclosporin; 10 mg/kg). Xenograft rejection was studied by light microscopy and immunofluorescence. The induced humoral response to porcine xenoantigens was documented by enzyme-linked immunosorbent assay using synthetic alpha-1,3-galactosyl epitopes coupled to bovine serum albumin. RESULTS: Graft life was extended from a mean of 3.6 +/- 0.5 days (n = 5) to a mean of 6.2 +/- 1.1 days (n = 5, p = 0.01). In comparison with controls, explanted grafts from medicated baboons demonstrated reduced infiltration with natural killer cells and macrophages, but increased evidence of complement-mediated rejection substantiated by increased deposition of immunoglobulin M, complement, and fibrin. In all baboons receiving transplants, levels of both immunoglobulin M and immunoglobulin G anti-galactose were significantly increased after transplantation, with immunoglobulin G levels remaining persistently elevated. CONCLUSIONS: These results indicate that cyclosporine-based triple immunosuppression marginally prolonged xenograft survival and appears to have reduced the natural killer cell and macrophage infiltrates. The immunosuppressive protocol, however, was not adequate to prevent the induced immunoglobulin M humoral response and prevent complement-mediated graft injury.