Absence of Gal epitope prolongs survival of swine lungs in an ex vivo model of hyperacute rejection

Bao Ngoc H. Nguyen, Agnes M. Azimzadeh, Carsten Schroeder, Thomas Buddensick, Tianshu Zhang, Amal Laaris, Megan Cochrane, Henk Jan Schuurman, David H. Sachs, James S. Allan, Richard N. Pierson

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Background: Galactosyl transferase gene knock-out (GalTKO) swine offer a unique tool to evaluate the role of the Gal antigen in xenogenic lung hyperacute rejection. Methods: We perfused GalTKO miniature swine lungs with human blood. Results were compared with those from previous studies using wild-type and human decay-accelerating factor-transgenic (hDAF+/+) pig lungs. Results: GalTKO lungs survived 132 ± 52 min compared to 10 ± 9 min for wild-type lungs (P = 0.001) and 45 ± 60 min for hDAF+/+ lungs (P = 0.18). GalTKO lungs displayed stable physiologic flow and pulmonary vascular resistance (PVR) until shortly before graft demise, similar to autologous perfusion, and unlike wild-type or hDAF+/+ lungs. Early (15 and 60 min) complement (C3a) and platelet activation and intrapulmonary platelet deposition were significantly diminished in GalTKO lungs relative to wild-type or hDAF+/+ lungs. However, GalTKO lungs adsorbed cytotoxic anti-non-Gal antibody and elaborated high levels of thrombin; their demise was associated with increased PVR, capillary congestion, intravascular thrombi and strong CD41 deposition not seen at earlier time points. Conclusions: In summary, GalTKO lungs are substantially protected from injury but, in addition to anti-non-Gal antibody and complement, platelet adhesion and non-physiologic intravascular coagulation contribute to Gal-independent lung injury mechanisms.

Original languageEnglish (US)
Pages (from-to)94-107
Number of pages14
JournalXenotransplantation
Volume18
Issue number2
DOIs
StatePublished - Jan 1 2011

Keywords

  • Xenotransplantation
  • alphaGal
  • antibodies
  • ex vivo lung perfusion
  • genetically engineered
  • hyperacute rejection
  • lung
  • swine

ASJC Scopus subject areas

  • Immunology
  • Transplantation

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    Nguyen, B. N. H., Azimzadeh, A. M., Schroeder, C., Buddensick, T., Zhang, T., Laaris, A., Cochrane, M., Schuurman, H. J., Sachs, D. H., Allan, J. S., & Pierson, R. N. (2011). Absence of Gal epitope prolongs survival of swine lungs in an ex vivo model of hyperacute rejection. Xenotransplantation, 18(2), 94-107. https://doi.org/10.1111/j.1399-3089.2011.00633.x