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Reducing the Threshold for Clinical Renal Xenotransplantation.

P antibodies have long been recognized as a major barrier to successful xenotransplantation of porcine organs. The primary manifestation of this problem is the binding of natural human or nonhuman primate (NHP) antibodies to carbohydrate epitopes on pig endothelial cells, which if not addressed results in hyperacute rejection or accelerated acute rejection. A wealth of data, collected over more than 2 decades, identify galactoseα1,3-galactose (αGal) as the most important carbohydrate xenoantigen. More recent studies have also implicated N-glycolylneuraminic acid (Neu5Gc) and an as yet unidentified moiety synthesized by β1, 4N-acetylgalactosaminyl transferase 2 (B4GalNT2). Recent advances in genome editing have paved the way for the elimination of carbohydrate xenoantigens by single-step deletion of multiple glycosyltransferase genes. In this issue of Transplantation, Martens et al report the impact of the deletion of the GGTA1 (αGal), CMAH (Neu5Gc) and B4GalNT2 genes on the xenoantigenicity of porcine peripheral blood mononuclear cells (PBMC). Flow cytometric crossmatch was performed using sera from renal transplant waitlisted patients and PBMC from wild type and genetically modified pigs. The results were clear: the addition of CMAH knockout (KO) and then B4GalNT2KO toGGTA1KO progressively reduced human antibody binding to the porcine cells. Indeed, 31% of patient sera showed a negative crossmatch (IgG and IgM) to the “triple KO” PBMC. This may prove to be a significant step forward in advancing renal xenotransplantation to the clinic. By substantially reducing the background contribution of carbohydrate xenoantigens to human antipig antibody binding, the authors attempted to examine a second important question: whether sensitized individuals on the waiting list possess anti-HLA class I antibodies that will cross-react with