Natural anti-galactose alpha1,3 galactose antibodies delay, but do not prevent the acceptance of extracellular matrix xenografts.

Naturally occurring antibodies to the galactose alpha1,3 galactose (alpha gal) epitope expressed on xenogeneic grafts are a major barrier to organ transplantation in humans. Porcine small intestinal submucosa (SIS) expresses the alpha gal epitope and is currently being used as a bioscaffold for tissue remodeling. To examine in detail the potential role of the alpha gal epitope in immune recognition of this acellular, avascular biomaterial, we have used mice which have a genetic disruption in the alpha1,3 galactosyltransferase gene (alpha gal(-/-)mice) and thus express natural anti-alpha gal antibodies in a manner similar to humans. It was found that alpha gal(-/-)mice produced IgM anti-alpha gal antibodies in addition to IgG1 SIS-specific antibodies, which did not bind to the alpha gal epitope. Histological examination of implant sites demonstrated an early inflammatory response that consisted predominantly of neutrophils in both alpha gal(+/+) and alpha gal(-/-)mice. However, while alpha gal(+/+)mice completely remodeled SIS implants by day 25, alpha gal(-/-)mice still exhibited some visible SIS together with inflammatory cellular infiltrates at this time point. Nevertheless, by day 35, the implant site in alpha gal(-/-)mice appeared to be entirely remodeled although a few acute inflammatory cells were still present. Immunization of alpha gal(-/-)mice with sheep erythrocytes to enhance anti-alpha 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-alpha gal antibodies do not influence the ability of xenogeneic extracellular matrices to serve as bioscaffolds for tissue remodeling.