A major obstacle to clinical applications of xenotransplantation is the expression of immunogenic xenoantigens that provide targets for immune recognition of xenografts, leading to activation of host immunity and consequent rejection or poor engraftment. Among the best known xenoantigens is the “αGal” epitope (Galα1− 3Galβ1−(3) 4GlcNAc-R, where R is an underlying glycoconjugate) characterized by Galili and colleagues. This epitope is widely expressed by most mammals other than old world primates and recognized by abundant circulating human anti-α-Gal antibodies (1). Such antibodies are universally induced after birth in humans via exposure to gut bacteria bearing similar epitopes (2), and the resulting difficulties in xenotransplantation (3) have even encouraged production of alpha1, 3-galactosyltransferase gene-knockout pigs (4) as a potential solution.

However, a second class of anti-carbohydrate xenoantibody recognize glycans carrying the non-human sialic acid N-glycolylneuraminic acid (Neu5Gc)(5–9). Unlike the case with αGal, the potential impact of Neu5Gc-glycans as xenoantigens is less well recognized. Here we address the similarities and differences between these two xenoantigens (see Table 1 for a summary and comparison), concluding that anti-Neu5Gc antibodies are of potential relevance not only to xenotransplantation, but also to allotransplantation and even to autotransplantation if methods are incorporated that require an ex-vivo culturing phase using animal materials, including stem-cell based therapies.