Pig alpha1, 3galactosyltransferase: a major target for genetic manipulation in xenotransplantation

Terminal carbohydrate residues of glycolipids and glycoproteins display polymorphism among as well as within various species. With the exception of Old World monkeys, great apes and man, the Gala1,3Gal structure is widely expressed in all mammals examined so far. The lack of expression of the glycosyltransferase responsible for the synthesis of Gala1,3Gal leads to the production of high titers of natural antibodies (NAb) against the Gala1,3Gal of other species. The inactivation of this gene occurred during early evolution of primates. Neutralization of viruses (e.g. retroviruses) carrying the epitope, by the pre-formed human NAb, indicates one possible evolutionary reason for the polymorphism of terminal carbohydrates among as well as within species. It has been shown that this epitope constitutes the major target, on pig endothelial cells (EC), for the pre-formed human NAb resulting in a hyperacute rejection (HAR) response. This currently makes transplantation of e.g. pig organs to humans impossible. Efforts are currently underway to prevent or to eradicate the expression of this epitope in transgenic pigs. Such pigs are likely to display a greatly increased resistance to the HAR.