Using α1,3-galactosyltransferase gene-knockout pig organs in nonhuman primates

Abstract

Purpose of review The aim of this article is to review the experience with α1,3-galactosyltransferase gene-knockout pig organ transplantation into nonhuman primates, and related in-vitro studies. Recent findings Since the first transplants of α1,3-galactosyltransferase gene-knockout pig organs into nonhuman primates were reported in 2005, there has been relatively little further in-vivo experience. This experience has demonstrated, however, the importance of pig non-Galα1,3Gal (Gal) antigens as targets for primate antipig antibodies. Several in-vitro studies have confirmed that, although the incidence and levels of anti-non-Gal antibodies in nonhuman primates and humans are significantly less when compared with total anti-pig antibodies (i.e., anti-Gal + anti-non-Gal), they can result in complement-mediated lysis of α1,3-galactosyltransferase gene-knockout pig cells. The in-vivo experience has also confirmed the importance of an immunosuppressive regimen that prevents an elicited anti-non-Gal antibody response, if acute humoral xenograft rejection is to be prevented. The antigen targets for anti-non-Gal antibodies remain uncertain. Evidence is accumulating that differences in the coagulation–anticoagulation systems between pig and primate result in coagulation dysregulation leading to the development of thrombotic microangiopathy and graft failure. Summary Although they have provided an advance over wild-type pigs as a source of organs, further genetic modification of α1,3-galactosyltransferase gene-knockout pigs is required to overcome the immune barriers of pig-to-nonhuman primate xenotransplantation.