The recent creation of pigs whose cells lack certain sugar molecules may bring the dream of xenotransplantation a step closer to reality. At first glance, α1,3-galactosyltransferase (α1,3GT) appears to be a fairly innocuous enzyme; in most mammalian species, α1,3GT participates in the production of carbohydrate chains that adorn cell surfaces in a wide variety of tissues.

However, evolutionary events from millions of years ago resulted in the elimination of α1,3GT expression in Old World monkeys, apes, and humans, and the α1,3Gal surface epitopes produced by this protein represent a primary obstacle to successful xenotransplantation. These carbohydrates trigger a significant human immune response; thus, the transplantation of tissues into humans from pigs or other donor species is generally doomed to failure as a result of hyperacute rejection (HAR), wherein the host immune system attacks and rapidly destroys the offending foreign tissue.

Researchers at PPL Therapeutics (Blacksburg, VA) and the University of Pittsburgh Medical Center (PA) took an important step toward reducing the threat of HAR by creating a line of pigs that lack functional α1,3GT (Science, online 19 December 2003). The group isolated fetal cells from a previously developed transgenic line with one functional copy of the α1,3GT gene, then used Clostridium difficile toxin A, which specifically kills cells producing α1,3Gal epitopes, to isolate lines completely lacking α1,3GT activity.

Apparently a spontaneous mutation abrogating enzyme function eliminated the second gene copy, and the researchers used the selected cell lines to generate four knockout piglets. α1,3Gal was undetectable in various tissues from these piglets, and pancreatic islet cells transplanted into α1,3GT-knockout mice failed to induce a substantial immune response relative to mice treated with wild-type cells.

These piglets have the potential to make an important contribution to the field of xenotransplantation, not only by eliminating a major roadblock to successful introduction of foreign tissue, but also, as co-author Yifan Dai points out, by aiding in the identification of other components involved in the triggering of HAR. With this transgenic line established, long-term experiments can begin to assess the potential for safe, rejection-free xenotransplantation, a source of considerable hope for would-be recipients of tissues with limited human donor pools.