Xenotransplantation: the importance of the Ga1 alpha 1,3Gal epitope in hyperacute vascular rejection

The transplantation of organs from other species into humans is considered to be a potential solution to the shortage of human donor organs. Organ tra nsplantation from pig to human, however, results in hyperacute rejection, i nitiated by the binding of human natural antidonor antibody and complement. The major target antigen of this natural antibody is the terminal disaccha ride Gal alpha 1,3Gal, which is synthesized by Gal beta 1,4GlcNAc alpha 1,3 -galactosyltransferase. Here we review our current knowledge of this key en zyme. A better understanding of structure, enzyme properties, and expressio n pattern of alpha 1,3-galactosyltransferase has opened up several novel th erapeutic approaches to prevent hyperacute vascular rejection. Cloning, and expression in vitro of the corresponding cDNA, has allowed to develop stra tegies to induce immune tolerance, and deplete or neutralize the natural xe noreactive antibody. Elucidation of the genomic structure has led to the pr oduction of transgenic animals that are lacking alpha 1,3-galactosyltransfe rase activity. A detailed knowledge of the enzyme properties has formed the basis of approaches to modify donor organ glycosylation by intracellular c ompetition. Study of the expression pattern of alpha 1,3-galactosyltransfer ase has helped to understand the mechanism of hyperacute rejection in disco rdant xenotransplantation, and that of complement-mediated, natural immunit y against interspecies transmission of retroviruses. (C) 1999 Elsevier Scie nce B.V. All rights reserved.