Natural anti-galactose α1,3 galactose antibodies delay, but do not prevent the acceptance of extracellular matrix xenografts

Naturally occurring antibodies to the galactose α 1,3 galactose (α gal) epitope expressed on xenogeneic grafts are a major barrier to organ transplantation in humans. Porcine small intestinal submucosa (SIS) expresses the α gal epitope and is currently being used as a bioscaffold for tissue remodeling. To examine in detail the potential role of the α gal epitope in immune recognition of this acellular, avascular biomaterial, we have used mice which have a genetic disruption in the α 1,3 galactosyl-transferase gene (α gal^-/- mice) and thus express natural anti-α gal antibodies in a manner similar to humans. It was found that α gal^-/- mice produced IgM anti-α gal antibodies in addition to IgG1 SIS-specific antibodies, which did not bind to the α gal epitope. Histological examination of implant sites demonstrated an early inflammatory response that consisted predominantly of neutrophils in both α gal^+/+ and α gal^-/- mice. However, while α gal^+/+ mice completely remodeled SIS implants by day 25, α gal^-/- mice still exhibited some visible SIS together with inflammatory cellular infiltrates at this time point. Nevertheless, by day 35, the implant site in α gal^-/- mice appeared to be entirely remodeled although a few acute inflammatory cells were still present. Immunization of α gal^-/- mice with sheep erythrocytes to enhance anti-α gal antibody levels led to a more robust early inflammatory response following implantation but did not change the ultimate fate of the graft. We conclude that, in contrast to xenotransplantation of whole organs, naturally-occurring anti-α gal antibodies do not influence the ability of xenogeneic extracellular matrices to serve as bioscaffolds for tissue remodeling.