Modifying the sugar icing on the transplantation cake

Area of Science:

• Transplant surgery
• Glycobiology
• Xenotransplantation

Background:

• Human anti-pig antibodies target specific carbohydrate epitopes, primarily galactose-α(1,3)-galactose (Gal), leading to hyperacute rejection in xenotransplantation.
• Preformed human antibodies initiate rapid graft destruction by binding to Gal antigens on pig vascular endothelium.

Purpose of the Study:

• To address the critical shortage of human organs for transplantation.
• To overcome immunological barriers in pig-to-human organ transplantation (xenotransplantation).

Main Methods:

• Genetic engineering to produce alpha(1,3)-galactosyltransferase (GT) knockout (GTKO) pigs, eliminating Gal epitopes.
• Deletion of other carbohydrate antigens, N-glycolylneuraminic acid and Sd(a) antigen, from pig cells.
• Genetic modifications to mitigate primate complement and coagulation activation.

Main Results:

• GTKO pigs significantly reduce hyperacute rejection mediated by anti-Gal antibodies.
• Combined genetic modifications have extended pig graft survival in nonhuman primates to many months.
• Clinical trials involving pig cell transplantation are ongoing.

Conclusions:

• Genetic engineering of pigs has substantially overcome key immunological barriers in xenotransplantation.
• These advancements pave the way for the future clinical use of pig organs in humans.
• Xenotransplantation holds promise for addressing organ donor shortages.