Gal/non-Gal antigens in pig tissues and human non-Gal antibodies in the GalT-KO era.

Our knowledge regarding Gal and non-Gal antigens in GalT-KO pig tissues can be summarized as α3Galactosyl-tranferase gene knock out eliminates the Galα3Galβ4GlcNAc-R antigen expression in pig tissues as well as anti-Gal antibody binding. Other Galα-terminating saccharides (e.g. iGb3 glycolipids and Galα2 determinants) may be present but have not been documented. α3Galactosyl-tranferase gene knock out slightly changes the carbohydrate antigen expression but no "new" antigens recognized by the human immune system have been found. Non-Gal antigens are both of protein and carbohydrate nature but their exact chemical structures are poorly defined. Regarding human non-Gal antibodies our knowledge is as Non-Gal antibodies exist naturally and increase in humans/non-human primate (NHP) receiving WT or GalT-KO pig grafts. Non-Gal antibodies with new antigen epitope recognition can be induced in humans/NHP after challenge by WT or GalT-KO pig grafts. Non-Gal antibodies react with both carbohydrates and proteins. Part of the protein reactivity is directed to glycoprotein carbohydrates chains. Non-Gal antibodies reacting with neuraminic acid terminated saccharides (both N-Acetyl and N-Glycoloyl variants) are present in humans/NHP. Anti-neuraminic acid antibodies are increased, as well as induced, after grafting pig organs into humans/NHP. Non-Gal antibodies does not cause hyperacute xenorejection but can be cytotoxic and cause xenoorgan damage. If humans sensitized to HLA antigens are at a higher risk of rejecting pig xenograft compared with non-sensitized individuals is not fully clarified. Clinical trials are needed to evaluate the relevance of non-Gal antigens/antibodies and for the xenofield to advance.