Natural anti‐pig antibodies in infant baboons

Dear Sir, Because of the specific problems associated with some complex congenital heart disease, for example, single ventricle pathology, heart transplantation is arguably the best therapeutic approach for these patients. However, because of the difficulty in obtaining suitably sized deceased human donor hearts for neonates and infants, and the poor results of mechanical cardiac assist devices in this age group, a strong case can be made for bridging with a genetically engineered pig cardiac xenograft.1 To investigate this possibility, we demonstrated that, although human infants develop IgM antibodies to wildtype (WT, ie, genetically unmodified) pig red blood cells (RBCs), they rarely develop antibodies to tripleknockout (TKO) pig RBCs (in which expression of all three of the known pig xenoantigens has been deleted).2 All Old World nonhuman primates, for example, baboons, differ from humans by expressing Nglycolylneuraminic acid (Neu5Gc) on their vascular endothelial cells. When the expression of Neu5Gc is deleted in the organsource pig, this exposes another carbohydrate xenoantigen(s) of hitherto unknown structure (sometimes known as the 4th xenoantigen),3,4 against which Old World nonhuman primates (but not humans) have natural antibodies. Organs from TKO pigs are therefore less than ideal for transplantation studies in these species. To investigate which genetically engineered pigs might prove optimal for organ transplantation into infant baboons, we have measured baboon serum IgM and IgG binding to RBCs from various pigs (Table 1).5 RBCs were selected as the target cells because they express only carbohydrate xenoantigens, but not protein xenoantigens. In our experience, the strength of serum IgM binding to pig RBCs correlates with the serum cytotoxicity toward these cells.4 There were significant increases in IgM and IgG binding to WT pig RBCs throughout infancy (Figure 1). There was sequentially less binding of IgM, and particularly of IgG, to DKO pig RBCs, and TKO