Galα(1,3)Gal, the Major Xenoantigen(s) Recognised in Pigs by Human Natural Antibodies

Abstract

The transplantation of pig organs to humans (xenotransplantation) is now receiving serious consideration because of the shortage of human donors for organ transplants of kidney, liver and heart, and of islet cell transplantation for diabetes. The problem with such xenografts would be hyperacute rejection--mediated by natural antibodies in humans to pig antigens, complement fixation to endothelial cells, and the rapid onset of intravascular coagulation. It is now clear that the major target of the natural IgM and IgG antibodies is the terminal carbohydrate epitope Gal alpha(1,3)Gal, formed by the alpha 1,3galactosyl transferase, which places a terminal galactose residue in an alpha-linkage to another galactose. The alpha 1,3galactosyl transferase in the pig gives rise to very high endothelial cell expression of Gal alpha(1,3)Gal, a ready explanation for the hyperacute rejection of vascularized organs. In addition the parenchuma of liver and kidneys have high levels of Gal alpha-(1,3)Gal. These tissues will all fail in a pig-to-human transplant in what can now be precisely defined in terms of antigen and antibody. We have already made some suggestions for removal of anti-Gal alpha(1,3)Gal antibodies and if the procedure were technically feasible xenotransplantation could be attempted now, especially in patients doomed to a certain death because of the absence of a donor (especially for liver where ex vivo perfusion could be performed). However, the immune system is far from simple, as is shown by the healthy status of mice lacking MHC Class I, Class II or both Class I & II molecules. Perhaps the curtain is about to go up to reveal a new scene! Islets differ from the other tissues and may well not undergo acute antibody-mediated hyperacute rejection--it will be of interest to see how these fare in xenotransplantation models or even in patients. Again, normal individuals do not have anti-islet antibodies; but a proportion of diabetic patients do have such antibodies--whether these will cause hyperacute or acute rejection or are markers of immunity of T-cell type, remains to be seen. Whatever, the area is exciting, is progressing rapidly and, as indicated elsewhere, within a few years we should know whether modified pig tissue can be grafted to some patients. The isolation of the cDNA clone encoding the pig alpha 1,3 galactosyl transferase is an essential first step in the production of a transgenic pig lacking the alpha 1,3Galactosyltransferase and therefore the Gal alpha(1,3)Gal epitope, and such animals could serve as donor for human transplantation.

Induction of molecular chimerism by gene therapy prevents antibody-mediated heart transplant rejection

“…In humans, apes and Old World primates, essentially all pig-reactive antibodies recognize the carbohydrate epitope Galα1-3Galβ1-4GlcNAc-R, (αGal). 4,5 αGal-reactive antibodies bind to αGal epitopes expressed on the surface of vascular endothelial cells within pig organs and initiate activation of the complement system, which in turn induces rapid destruction of endothelial cells and loss of vascular integrity culminating in hyperacute rejection. 6 In the absence of complement, αGal-reactive antibodies cause a delayed form of graft rejection referred to as delayed xenograft rejection or acute vascular rejection.…”

Remodeling of the Major Pig Xenoantigen by N-Acetylglucosaminyltransferase III in Transgenic Pig

“…In this study, the control 1 donor heart was rejected at 25 min in the recipient cynomolgus monkey with an average CH50 unit and a slightly high IgM titer. Therefore, the case of control 2, with a relatively low level of IgM and IgG titer (48), which was rejected in 165 min after transplantation, might be a rare case for the pig to cynomolgus monkey combination.…”

Effect of Redox Modulation on Xenogeneic Target Cells: The Combination of Nitric Oxide and Thiol Deprivation Protects Porcine Endothelial Cells from Lysis by IL-2-Activated Human NK Cells

“…Other recognition structures on human NK cells for porcine EC may include CD2 (62) or leukocyte integrins (65), which may be involved in the recognition of PAEC by human NK cells. It also has been suggested that human NK cells somehow recognize the ␣-galactosyl epitope expressed on pig cells (66) recognized by natural Abs and responsible for hyperacute rejection of xenografts in appropriate model systems (67)(68)(69). Although the capacity of human lymphocytes to recognize porcine MHC has been reported, this has been only for recognition by CD4 ϩ T cells that resulted in proliferation of those human T cells (70).…”