Intravenous infusion of Galα1-3Gal oligosaccharides in baboons delays hyperacute rejection of porcine heart xenografts

Background. Hyperacute rejection (HAR) of pig-to-primate discordant xenografts is caused by the deposition of preexisting natural antibodies that recognize Gal alpha 1-3Gal (alpha Gal)-terminating oligosaccharides on glycoproteins and glycolipids, followed by complement-mediated lysis of the graft's endothelium, In vitro, these natural xenoantibodies can be blocked by alpha Gal-containing oligosaccharides. We undertook in vivo pig-to-baboon cardiac xenotransplantation experiments to evaluate 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 extent of neutralization of anti-alpha Gal antibody activity, alpha Gal trisaccharide (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 heterotopic heart xenografts were continuously infused with alpha Gal pentasaccharide for 4-5 hr, maintaining the serum oligosaccharide concentration in the millimolar range, Results, Pharmacokinetic analysis indicated that the oligosaccharides were rapidly cleared from the blood, with a serum half-life of 50 min, In the period during which blood oligosaccharide concentration was above 1 mM, as determined by high-pressure liquid chromatography, the serum cytotoxic activity against porcine cells was completely abolished, HAR of the xenograft was inhibited during the infusions, although there was some histological and immunohistological evidence of antibody-mediated injury on biopsies taken at the end of this period, Conclusions, Intravenous alpha Gal oligosaccharides, by inhibiting anti-alpha Gal antibody activity, delay but do not abolish the onset of HAR.