Heart transplantation in baboons using α1,3-galactosyltransferase gene-knockout pigs as donors: initial experience

Abstract

Hearts from alpha1,3-galactosyltransferase knockout pigs (GalT-KO, n = 8) were transplanted heterotopically into baboons using an anti-CD154 monoclonal antibody-based regimen. The elimination of the galactose-alpha1,3-galactose epitope prevented hyperacute rejection and extended survival of pig hearts in baboons for 2-6 months (median, 78 d); the predominant lesion associated with graft failure was a thrombotic microangiopathy, with resulting ischemic injury. There were no infectious complications directly related to the immunosuppressive regimen. The transplantation of hearts from GalT-KO pigs increased graft survival over previous studies.

Generation of GGTA1 biallelic knockout pigs via zinc-finger nucleases and somatic cell nuclear transfer

“…Therefore, to eliminate the xenoantigen, the pig GGTA1 gene has been knocked out using conventional methods [8,13]. Furthermore, solid organs from GGTA1 knockout pigs displayed significantly improved survival in pig-to-baboon xenotransplantation experiments [2,4]. However, HR technology has low efficiency and introduces exogenous drug resistance genes.…”

Porcine UL16-Binding Protein 1 Expressed on the Surface of Endothelial Cells Triggers Human NK Cytotoxicity through NKG2D

“…Currently, insufficient long-term graft function prevents the successful clinical application of xenotransplantation (2). Nevertheless, advances in preventing hyperacute rejection in preclinical nonhuman primate models using genetically engineered pigs as organ source indicate that all coagulation disorders, Abs to non-Gal Ags, and cellular immunity play a role in xenogeneic responses (3)(4)(5). There are also several lines of evidence that NK cells may be a factor in delayed rejection of porcine xenografts (6).…”

“…Many of the inhibitory NK receptors recognize MHC class I molecules, and therefore allow NK cells to discriminate between normal self, nonself, and altered cells (16). Porcine endothelial cells (pEC) 3 are susceptible to human NK cell-mediated lysis possibly due to the inability of swine leukocyte Ag class I molecules to signal through human NK inhibitory receptors (17,18). In contrast, the activation of human NK cells by potential ligands expressed on pEC may be equally, or more, important.…”

Les xénogreffes finiront-elles par être acceptées ?

“…Les premiers résultats dans des modèles de greffes cardiaque et rénale sous traitement immunosuppresseur fort (mycophénolate mofétil, stéroïdes, splénectomie et/ou thymectomie) montrent une absence d'AVR et une survie plus longue, jusqu'à 100 jours [30]. Cependant, en fonction des traitements, des signes plus ou moins prononcés de microangiopathie thrombotique ont été observés dans la plupart des greffons [31,32]. Cette microangiopathie évoque l'induction d'anticorps dirigés contre d'autres déterminants que le Galα1-3Gal.…”