Prolonged survival of musculoskeletal xenografts with combined cyclosporine and 15-deoxyspergualin

This study was undertaken to evaluate the feasibility of performing vascula rized musculoskeletal xenografts between mice and rats using immunosuppress ion. Vascularized musculoskeletal grafts were harvested from the hind limb of C57BL/6J (B6) mice, transplanted heterotopically into Lewis rats, and re vascularized by microanastomoses of the graft artery and the recipient femo ral artery and the graft vein to the recipient femoral vein. Recipient rats were divided into four groups. Group 1 received no immunosuppression (n = 10), group 2 was treated with cyclosporine (10 mg/kg/day; n = 10), group 3 was treated with 15-deoxyspergualin (5 mg/kg/day; n = 10), and group 4 rece ived both cyclosporine and 15-deoxyspergualin (n = 10). Graft survival was directly examined on postoperative days 4, 7, and 14. In vitro assays were performed using mixed lymphocyte reactions and anti-donor cytotoxic antibod y assays to assess the recipient's immune response. Grafts were examined by histology and immunohistochemistry. All grafts in group 1 were rejected by day 4. In groups 2 and 3, all grafts were rejected by day 7. In group 4, however, 8 of 10 recipients had viable grafts on day 14. Data from mixed lymphocyte reactions showed that cell-me diated immune responses were uniformly suppressed in groups 2, 3, and 4 com pared with group 1. However, anti-donor antibody production was only partly suppressed in groups 2 and 3, suggesting that graft rejection was primaril y caused by circulating cytotoxic anti-donor antibodies in groups 1, 2, and 3. Histologic observations in groups 1, 2, and 3 confirmed the important r ole of the humoral mechanism in xenograft rejection. Furthermore, immunohis tochemical results demonstrated that the small vessels in the rejected graf ts showed anti-rat immunoglobulin and complement depositions. Only a combin ation therapy of cyclosporine and 15-deoxyspergualin attenuated the rejecti on of xenografts.