The Possible Role of Anti-Neu5Gc as an Obstacle in Xenotransplantation

Abstract

Seventy to ninety percentage of preformed xenoreactive antibodies in human serum bind to the galactose-α(1,3)-galactose Gal epitope, and the creation of Gal knockout (KO) pigs has eliminated hyperacute rejection as a barrier to xenotransplantation. Now other glycan antigens are barriers to move ahead with xenotransplantation, and the N-glycolyl neuraminic acid, Neu5Gc (or Hanganutziu-Deicher antigen), is also a major pig xenoantigen. Humans have anti-Neu5Gc antibodies. Several data indicate a strong immunogenicity of Neu5Gc in humans that may contribute to an important part in antibody-dependent injury to pig xenografts. Pig islets express Neu5Gc, which reacted with diet-derived human antibodies and mice deleted for Neu5Gc reject pancreatic islets from wild-type counterpart. However, Neu5Gc positive heart were not rejected in Neu5Gc KO mice indicating that the role of Neu5Gc-specific antibodies has to be nuanced and depend of the graft situation parameters (organ/tissue, recipient, implication of other glycan antigens). Recently generated Gal/Neu5Gc KO pigs eliminate the expression of Gal and Neu5Gc, and improve the crossmatch of humans with the pig. This review summarizes the current and recent experimental and (pre)clinical data on the Neu5Gc immunogenicity and emphasize of the potential impact of anti-Neu5Gc antibodies in limiting xenotransplantation in humans.

Effects of human TFPI and CD47 expression and selectin and integrin inhibition during GalTKO.hCD46 pig lung perfusion with human blood

“…[36][37][38] When these genetic modifications are combined, GalTKO.hCD46 porcine lungs exhibit early graft failure associated with inflammatory and coagulation dysregulation. This observation justifies efforts to explore: (1) removing the two other dominant carbohydrate targets (Neu5Gc; β4 Gal) 39 ; (2) adding coagulation pathway regulatory genes such as hCD39, 40 hTBM, 41 and hEPCR, 42 and increasing intensity and prevalence of endothelial expression of hTFPI 15 to improve coagulation cascade dysregulation; and (3) expressing self-recognition receptors such as HLA-E 33 and increasing intensity and/or prevalence of endothelial expression of hCD47 [17][18][19] to blunt innate immune inflammation.…”

Where’s the Beef? Understanding Allergic Responses to Red Meat in Alpha-Gal Syndrome

“…These existing Abs are typically IgM, IgA, or IgG isotypes, with IgG isotypes being the most abundant (25,30,31). These alphagalspecific Abs help the immune system distinguish self from nonself and can drive acute organ rejection of xenogenic organ transplants (32,33). They also increase the efficiency with which the host immune system neutralizes and resists alphagalexpressing pathogens (3,34).…”

Cardiac Xenotransplantation: Progress in Preclinical Models and Prospects for Clinical Translation

“…CMAH KO pigs ( 67 ). Later, Tector’s group has produced three carbohydrate antigen knockout (TKO) pigs (i.e., GTKO.CMAHKO.B4GALNT2KO), which included deletion of B4GALNT2 responsible for SDa antigen along with GT and CMAH genes ( 26 , 31 , 73 ). They demonstrated that the binding of human IgG and IgM antibodies to peripheral blood mononuclear cells and red blood cells from triple knockout pigs was significantly reduced.…”