CARDIAC XENOGRAFTS BETWEEN PRIMATE SPECIES PROVIDE EVIDENCE FOR THE IMPORTANCE OF THE ALPHA-GALACTOSYL DETERMINANT IN HYPERACUTE REJECTION

Transplants performed between phylogenetically disparate species are s ubject to hyperacute rejection initiated by binding of xenoreactive na tural Abs to endothelium in the donor organ. Binding of these Abs acti vates complement, leading to tissue injury and destruction of the graf t. Human xenoreactive natural Abs recognize Gal alpha 1-3Gal beta 1-4G lcNAc (galactose alpha 1-3galactose beta 1-4-(N) under bar-acetylgluco same); however, the relative importance of this Ag in graft rejection has not been proved. The present study was conducted to test the poten tial importance of alpha-galactosyl (alpha-Gal) determinants in the pa thogenesis of hyperacute rejection. To this end, hearts (n=3) from New World monkeys (Saimiri scureus, squirrel monkey), which can synthesiz e Gal alpha 1-3Gal, were transplanted heterotopically into Old World m onkeys (Papio species, baboon), which do not synthesize Gal alpha 1-3G al determinants and which have circulating anti-alpha Gal Abs. The xen ografts were rejected in 51 to 56 min (mean +/- SD = 53.3 +/- 2.5), re sults similar to those observed in porcine grafts transplanted into ba boons. Histologic analysis of the hearts revealed thrombosis and intra parenchymal hemorrhage and immune deposits consisting of IgM, C1q, C3, C4, C5b, and the membrane attack complex, but not properdin or factor B of the recipient deposited on graft endothelium. Sera obtained from baboons after perfusion of squirrel monkey kidneys revealed depletion of alpha-Gal-specific Abs and anti-pig endothelial cell Abs. These fi ndings provide strong evidence that the Abs that accumulate in New Wor ld monkey organs during perfusion with baboon blood are the same Abs t hat would accumulate in a porcine organ transplanted into a primate an d suggest that hyperacute rejection is not necessarily a reflection of phylogenetic distance but that the expression of terminal alpha-Gal r esidues provides an adequate target to initiate that process.