Anti-non-Gal porcine endothelial cell antibodies in acute humoral xenograft rejection of hDAF-transgenic porcine hearts in cynomolgus monkeys.
BACKGROUND
Anti-Gal alpha 1-3Gal (Gal) antibodies play a major role in hyperacute rejection and acute humoral xenograft rejection (AHXR) in porcine-to-nonhuman primate transplantation. The role of anti-non-Gal antibodies in AHXR is less well defined.


METHODS
Eleven cynomolgus monkeys received a heterotopic heart transplant from a human decay-accelerating factor transgenic pig, and maintenance immunosuppression with cyclosporin A or tacrolimus, steroids, mycophenolate sodium or mycophenolate mofetil, and in 10 animals the Gal-containing soluble glycoconjugate GAS914. Six ended with AHXR (6 to 78 day survival) and five did not show AHXR (9 to 36 day survival). Anti-Gal antibodies were depleted in vivo with GAS914, or in vitro with Gal-coated Sepharose beads. IgM- and IgG-class anti-non-Gal antibodies in serum depleted of anti-Gal antibodies were measured by flow cytometry using porcine endothelial target cells.


RESULTS
Compared with pre-transplant values, all six recipients with AHXR showed a substantially higher level of anti-non-Gal IgM antibodies at rejection; in five animals there was also an increase in IgG-class antibodies. There was no relevant change in recipients without AHXR. AHXR at time of cessation of heart contraction could be preceeded by a steady increase in antibody level starting 2 to 3 weeks earlier.


CONCLUSIONS
AHXR is invariably associated with increased circulating anti-non-Gal antibodies. These antibodies are not observed in recipients without AHXR, and five of six recipients with AHXR were adequately depleted of anti-Gal antibodies by maintenance GAS914. This indicates that anti-non-Gal antibodies play a significant role in the pathogenesis of AHXR. Also, the assessment of these antibodies could be used as an early monitor of AHXR.
Transplantation Immunology Laboratory, Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA 94305-5407, USA.
Tuan T
TT
Lam
Ricardo
R
Paniagua
Giridhar
G
Shivaram
Henk-Jan
HJ
Schuurman
Dominique C
DC
Borie
Randall E
RE
Morris
D000208:Acute Disease; D000818:Animals; D030801:Animals, Genetically Modified; D000910:Antibodies, Heterophile / Q000276:immunology*; D004187:Disaccharides / Q000276:immunology*; D042783:Endothelial Cells / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D008252:Macaca fascicularis; D013552:Swine; D014183:Transplantation, Heterologous / Q000276:immunology*; D014312:Trisaccharides / Q000494:pharmacology
D000910:Antibodies, Heterophile; D004187:Disaccharides; D014312:Trisaccharides; C076569:alpha-galactosyl epitope; C055075:galactosyl-(1-3)galactose