Acute rejection is associated with antibodies to non-Gal antigens in baboons using Gal-knockout pig kidneys

Abstract

We transplanted kidneys from alpha1,3-galactosyltransferase knockout (GalT-KO) pigs into six baboons using two different immunosuppressive regimens, but most of the baboons died from severe acute humoral xenograft rejection. Circulating induced antibodies to non-Gal antigens were markedly elevated at rejection, which mediated strong complement-dependent cytotoxicity against GalT-KO porcine target cells. These data suggest that antibodies to non-Gal antigens will present an additional barrier to transplantation of organs from GalT-KO pigs to humans.

Double-Negative T Cells, Activated by Xenoantigen, Lyse Autologous B and T Cells Using a Perforin/Granzyme-Dependent, Fas-Fas Ligand-Independent Pathway

“…While treatment with immunosuppressive drugs has shown substantial progress in allotransplantation, there are currently no immunosuppressive drugs capable of preventing xenograft rejection in a pig-to-nonhuman primate transplantation model (1,6,7). Furthermore, current immunosuppressive protocols that prevent xenograft rejection in nonhuman primates are too toxic for patient use.…”

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).…”

Anti-Gal and Anti-Non Gal Antibody Barriers in Xenotransplantation

“…These pigs have been generated by targeted disruption (knockout) of the 1,3galactosyltransferase gene (Phelps et al, 2003;KoblerSimond et al, 2004;Yamada et al, 2005;Takahagi et al, 2005;McGregor et al, 2011). These pigs lack -gal epitopes and their organs do not induce an anti-Gal response when transplanted into primates (Chen et al, 2005;Ezzelarab et al, 2006;Hisashi et al, 2008;Yeh et al, 2010). Thus, in contrast to rapid (hyperacute) rejection of wild type (WT) pig organs in monkeys (observed within <1h to several hours), pig organs from 1,3galactosyltransferase knockout pigs (1,3GT KO pigs) survive in monkeys for weeks to several months prior to rejection Chen et al, 2005;Kuwaki et al, 2005;Tseng et al, 2005;Hisashi et al, 2008).…”

“…These pigs lack -gal epitopes and their organs do not induce an anti-Gal response when transplanted into primates (Chen et al, 2005;Ezzelarab et al, 2006;Hisashi et al, 2008;Yeh et al, 2010). Thus, in contrast to rapid (hyperacute) rejection of wild type (WT) pig organs in monkeys (observed within <1h to several hours), pig organs from 1,3galactosyltransferase knockout pigs (1,3GT KO pigs) survive in monkeys for weeks to several months prior to rejection Chen et al, 2005;Kuwaki et al, 2005;Tseng et al, 2005;Hisashi et al, 2008). In the absence of anti-Gal response the next immune obstacle in xenotransplantation became apparent-the production of anti-non gal Abs against xenoantigens of the graft which are not -gal epitopes.…”

“…Studies of xenotransplantation under immunosuppression of wild type pig heart and kidney into monkeys demonstrated anti-non gal Ab production, even if the xenograft was rejected within few days (Buhler et al, 2003;Lam et al, 2004;Chen et al, 2005;Ezzelarab et al, 2006). Transplantation of 1,3GT KO pig heart or kidney in monkeys subjected to a variety of immunosuppressive protocols resulted in survival of the xenografts for much longer periods (from several days up to 3 months [even up to 6 months in one recipient of heart xenograft]) than survival of xenografts from wild type pigs presenting multiple -gal epitopes Chen et al, 2005;Tseng et al, 2005;Chen et al, 2006;Ezzelarab et al, 2006;Hisashi et www.intechopen.com al., 2008). Ultimately, all xenografts were rejected and the recipient monkeys were found to produce anti-non gal Abs which could be detected in vitro as Abs binding to 1,3GT KO pig cells.…”