The generation of pigs devoid of Galα1,3Galβ1,4GlcNAc (Gal) residues has stimulated interest in non-Gal Ags as potentially important targets for Ab binding leading to rejection of pig organ xenografts in humans. Although N-glycolylneuraminic acid (NeuGc) epitopes, which are widely expressed on the endothelial cells of all mammals except humans, are likely targets of anti - non-Gal Abs, this aspect has not been investigated intensively owing to the absence of an appropriate animal model. In this study, we used CMAH -/- mice, which are completely deficient in NeuGc and thus produce anti-NeuGc Abs. Sera obtained from CMAH-/- mice and healthy human volunteers having anti-NeuGc Abs initiated complement-mediated lysis against CMAH+/+ cells in vitro. The cytotoxic activity of anti-NeuGc Abs was also determined in vivo (i.e., NeuGc-expressing CMAH+/+ mouse splenocytes that had been i.v. injected were completely eliminated in syngeneic CMAH-/- mice). CMAH-/- mice rejected the islets transplanted from syngeneic CMAH+/+ mice. Thus, the anti-NeuGc Ab-mediated response may be crucially involved in xenograft loss. This is the first direct demonstration of the immunogenic property of NeuGc determinants as targets of the corresponding Abs in CMAH+/+-to-CMAH-/- transplantation setting.
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