INTRAVENOUS-INFUSION OF GAL-ALPHA-1-3GAL OLIGOSACCHARIDES IN BABOONS DELAYS HYPERACUTE REJECTION OF PORCINE HEART XENOGRAFTS

Background. Hyperacute rejection (HAR) of pig-to-primate discordant xe nografts is caused by the deposition of preexisting natural antibodies that recognize Gal alpha 1-3Gal (alpha Gal)-terminating oligosacchari des on glycoproteins and glycolipids, followed by complement-mediated lysis of the graft's endothelium, In vitro, these natural xenoantibodi es can be blocked by alpha Gal-containing oligosaccharides. We underto ok in vivo pig-to-baboon cardiac xenotransplantation experiments to ev aluate free oligosaccharides as inhibitors of HAR. Methods, Initial 15 -min intravenous infusions of alpha Gal-oligosaccharides into baboons were used to measure pharmacokinetic parameters, and to assess the ext ent of neutralization of anti-alpha Gal antibody activity, alpha Gal t risaccharide (Gal alpha 1-3Gal beta 1-4GlcNAc) or pentasaccharide (Gal alpha 1-3Galp1-4GlcNAc beta 1-3Gal beta 1-4Glc) was administered at 0 .5 mmol/kg into baboons, Next, two baboons that received porcine heter otopic heart xenografts were continuously infused with alpha Gal penta saccharide for 4-5 hr, maintaining the serum oligosaccharide concentra tion in the millimolar range, Results, Pharmacokinetic analysis indica ted that the oligosaccharides were rapidly cleared from the blood, wit h a serum half-life of 50 min, In the period during which blood oligos accharide concentration was above 1 mM, as determined by high-pressure liquid chromatography, the serum cytotoxic activity against porcine c ells was completely abolished, HAR of the xenograft was inhibited duri ng the infusions, although there was some histological and immunohisto logical evidence of antibody-mediated injury on biopsies taken at the end of this period, Conclusions, Intravenous alpha Gal oligosaccharide s, by inhibiting anti-alpha Gal antibody activity, delay but do not ab olish the onset of HAR.