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The present study aimed to evaluate the effect of plasma exchange (PE) in combination with certain immunosuppressive agents on the survival of guinea-pig hearts in C6-deficient (C6−) rats. To deplete macrophages, we gave liposome-encapsulated dichloromethylene diphosphonate (Lip-Cl2MDP) intravenously (i.v.) in a dose of 10 mg/kg on day 2 before transplantation and every 5 days until rejection. Deoxyspergualin (DSG) was also given i.v. in a dose of 10 mg/kg/day from day −2 until rejection. Plasma exchange was performed 1 day before xenografting. All animals were splenectomized just before heart transplantation. Heart xenografts were evaluated twice daily and harvested at the time of rejection. The serum levels of anti-guinea-pig xenoreactive antibody (IgM, IgG) were measured using enzyme-linked immunosorbent assay (ELISA). Graft survival was 2.8 ± 0.5 days in control rats, and 4.0 ± 0.3 days with PE alone. A combination of PE with Lip-Cl2MDP or DSG did not improve the results (4.2 ± 0.6 days vs. 4.8 ± 0.6 days, respectively). While in rats treated with PE and the combination of Lip-Cl2MDP and DSG, graft survival was significantly prolonged (6.9 ± 1.1 days, P < 0.01 vs. controls). In untreated control rats, xenoreactive antibody (IgM, IgG) levels decreased immediately after PE, but their levels rapidly returned to normal. In rats treated with DSG or DSG + Lip-Cl2MDP, the IgM levels remained low during the observation period. Immunohistochemistry showed that macrophage infiltration into the graft was suppressed in Lip-Cl2MDP-treated groups at the time of rejection. Our results demonstrate that sustained suppression of antibody levels can be achieved by PE in combination with DSG and xenograft survival is further prolonged in macrophage-depleted C6− rats. These findings suggest that strategies targeting antibody and macrophages may be useful in prolonging xenograft survival.