Cardiac xenotransplantation

The severe shortage of human donor hearts has prompted several investigators to develop alternative strategies using cross-specie organs or xenografts. Unlike human allotransplantation, in which the important antigenic differences between donor and recipient are confined to the major histocompatibility and blood group antigens, xenotransplantation is confronted with the potential for multiple antigenic differences. In the pig-to-primate model of xenotransplantation, the primary obstacle to cross-species transplantation has been hyperacute rejection mediated by complement fixing antibodies directed against galactose α1,3-galactose (Gal α1,3-Gal) epitopes on the pig endothelium. Conventional immunosuppression is unable to overcome hyperacute rejection; however, recent efforts in molecular biology have focused on genetically engineering porcine donors to express human proteins in their tissue. Transgenic pigs that express human complement regulatory proteins on their endothelium have been developed. Heterotopic transplantation of these transgenic donor hearts have had only moderate success. Alternative approaches attempt to eliminate the Gal α1,3-Gal epitopes by genetically 'knocking out' the enzyme necessary for its synthesis, or to reduce the expression of Gal α1,3-Gal epitopes by genetically inserting enzymes that redirect precursor molecules into alternative synthetic pathways. The technology to knock out the necessary enzymes in pigs is not yet available; however, pigs expressing the H-transferase gene have been developed and show reduced levels of Gal α1,3-Gal epitopes. Although this 'new breed' of transgenic pigs may overcome the barrier of hyperacute rejection, special strategies will need to be developed that target the next barrier of xenograft rejection.