Renal and cardiac endothelial heterogeneity impact acute vascular rejection in pig-to-baboon xenotransplantation

C. Knosalla, K. Yazawa, A. Behdad, N. Bodyak, H. Shang, L. Bühler, S. Houser, B. Gollackner, A. Griesemer, I. Schmitt-Knosalla, H. J. Schuurman, M. Awwad, D. H. Sachs, D. K C Cooper, K. Yamada, A. Usheva, S. C. Robson

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

Xenograft outcomes are dictated by xenoantigen expression, for example, Gal α1, 3Gal (Gal), but might also depend on differing vascular responses. We investigated whether differential vascular gene expression in kidney and cardiac xenografts correlate with development of thrombotic microangiopathy (TM) and consumptive coagulation (CC). Immunosuppressed baboons underwent miniswine or hDAF pig kidney (n = 6) or heart (n = 7), or Gal-transferase gene-knockout (GalT-KO) (thymo)kidney transplantation (n = 14). Porcine cDNA miniarrays determined donor proinflammatory, apoptosis-related and vascular coagulant/fibrinolytic gene expression at defined time points; validated by mRNA, protein levels and immunopathology. hDAF-transgenic and GalT-KO xenografts, (particularly thymokidneys) exhibited prolonged survival. CC was seen with Gal-expressing porcine kidneys (3 of 6), only 1 of 7 baboons postcardiac xenotransplantation and was infrequent following GalT-KO grafts (1 of 14). Protective-type genes (heme oxygenase-I, superoxide dismutases and CD39) together with von Willebrand factor and P-selectin were upregulated in all renal grafts. Transcriptional responses in Gal-expressing xenografts were comparable to those seen in the infrequent GalT-KO rejection. In cardiac xenografts, fibrin deposition was associated with increased plasminogen activator inhibitor-1 expression establishing that gene expression profiles in renal and cardiac xenografts differ in a quantitative manner. These findings suggest that therapeutic targets may differ for renal and cardiac xenotransplants.

Original languageEnglish (US)
Pages (from-to)1006-1016
Number of pages11
JournalAmerican Journal of Transplantation
Volume9
Issue number5
DOIs
StatePublished - May 2009

Keywords

  • Gene expression
  • Heart
  • Kidney
  • Vasculature
  • Xenotransplantation

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

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