Methods of inhibiting the hyperacute antibody-mediated rejection that occurs when pig organs are transplanted into primates have been investigated using the baboon as a potential recipient. Baboons were treated with different regimens that included combinations of (1) splenectomy, (2) pharmacologic immunosuppression (CsA, cyclophosphamide, corticosteroids ± methotrexate), and (3) intravenous infusion of oligosaccharides. The cytotoxicity of the serum was then assessed on cultures of pig kidney cells (PK15). Unmodified serum caused approximate 65-100% pig cell destruction. Splenectomy and/or pharmacologic immunosuppression, and infusions of dextran, dextrose or mannitol, did not result in any reduction of cytotoxicity. Infusions of melibiose and/or arabinoga-lactan, both of which have terminal non-reducing a-galactose, however, decreased relative PK15 cell damage significantly in a dose-dependent manner. At high concentrations (< 50 g/hr), complete inhibition of cytotoxicity was achieved in 4 of 15 baboons. The ex-tracorporeal immunoadsorption of baboon serum utilizing immunoaffinity columns of melibiose also resulted in a significant reduction (of 80%) in cytotoxic effect. In 1 baboon, melibiose and arabinogalactan infusion delayed vascular rejection of a pig cardiac xenograft from 10 min to about 12 hr, at which time the baboon died from the toxic effects of the carbohydrate infusion. These observations (1) add further support to the role that anti-a-galactosyl antibodies play in the hyperacute rejection of pig tissues transplanted into primates, and (2) demonstrate that serum cytotoxicity can be reduced by the intravenous infusion of a-galac-tosyl oligosaccharides or by extracorporeal immunoadsorption using these carbohydrates. © 1994 by Williams and Wilkins.