α1,3‐Galactosyltransferase knockout pigs are available for xenotransplantation: Are glycosyltransferases still relevant?

In the early 1990s, the Galalpha(1,3)Gal carbohydrate linkage was found to be the major xenoepitope causing hyperacute rejection. This carbohydrate, the antibodies that bind to it, and the enzyme that produces it (alpha1,3-galactosyltransferase) were the foci of research by many groups. Nearly a decade later, alpha1,3-galactosyltransferase knockout pigs were finally produced; hyperacute rejection could be avoided in these pigs. Having achieved this goal, enthusiasm declined for the study of glycosyltransferases and their carbohydrate products. To examine whether this decline was premature, we evaluate whether gene deletion has indeed solved the initial rejection problem or, in fact, created new problems. This review addresses this by examining the impact of the gene deletion on cell surface carbohydrate. Surprisingly, Galalpha(1,3)Gal is still present in alpha1,3-galactosyltransferase knockout animals: it is possibly synthesized on lipid by iGb3 synthase. Furthermore, removal of alphaGal resulted in the exposure of the N-acetyllactosamine epitope. This exposed epitope can bind natural antibodies and perhaps should be capped by transgenic expression of another transferase. We believe the continued study of glycosyltransferases is essential to examine the new issues raised by the deletion of alpha1,3-galactosyltransferase.