Anti-non-Gal porcine endothelial cell antibodies in acute humoral xenograft rejection of hDAF-transgenic porcine hearts in cynomolgus monkeys

Tuan T. Lam, Ricardo Paniagua, Giridhar Shivaram, Henk Jan Schuurman, Dominique C. Borie, Randall E. Morris

Research output: Contribution to journalArticle

48 Scopus citations

Abstract

Background: Anti-Galα1-3Gal (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.

Original languageEnglish (US)
Pages (from-to)531-535
Number of pages5
JournalXenotransplantation
Volume11
Issue number6
DOIs
StatePublished - Nov 1 2004

Keywords

  • Acute humoral xenograft rejection
  • Anti-Gal antibody
  • Anti-endothelial cell antibody
  • Anti-non-Gal antibody
  • Anti-porcine antibody
  • Cynomolgus monkey
  • Non-human primate
  • hDAF

ASJC Scopus subject areas

  • Immunology
  • Transplantation

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