Early graft failure of GalTKO pig organs in baboons is reduced by expression of a human complement pathway-regulatory protein

Agnes M. Azimzadeh, Sean S. Kelishadi, Mohamed B. Ezzelarab, Avneesh K. Singh, Tiffany Stoddard, Hayato Iwase, Tianshu Zhang, Lars Burdorf, Evelyn Sievert, Chris Avon, Xiangfei Cheng, David Ayares, Keith A. Horvath, Philip C. Corcoran, Muhammad M. Mohiuddin, Rolf N. Barth, David K.C. Cooper, Richard N. Pierson

Research output: Contribution to journalArticlepeer-review

Abstract

We describe the incidence of early graft failure (EGF, defined as loss of function from any cause within 3 days after transplant) in a large cohort of GalTKO pig organs transplanted into baboons in three centers, and the effect of additional expression of a human complement pathway-regulatory protein, CD46 or CD55 (GalTKO.hCPRP). Baboon recipients of life-supporting GalTKO kidney (n = 7) or heterotopic heart (n = 14) grafts received either no immunosuppression (n = 4), or one of several partial or full immunosuppressive regimens (n = 17). Fourteen additional baboons received a GalTKO.hCPRP kidney (n = 5) or heart (n = 9) and similar treatment regimens. Immunologic, pathologic, and coagulation parameters were measured at frequent intervals. EGF of GalTKO organs occurred in 9/21 baboons (43%). hCPRP expression reduced the GalTKO EGF incidence to 7% (1/14; P < 0.01 vs. GalTKO alone). At 30 mins, complement deposits were more intense in organs in which EGF developed (P < 0.005). The intensity of peri-transplant platelet activation (as β-thromboglobulin release) correlated with EGF, as did the cumulative coagulation score (P < 0.01). We conclude that (i) the transgenic expression of a hCPRP on the vascular endothelium of a GalTKO pig reduces the incidence of EGF and reduces complement deposition, (ii) complement deposition and platelet activation correlate with early GalTKO organ failure, and (iii) the expression of a hCPRP reduces EGF but does not prevent systemic coagulation activation. Additional strategies will be required to control coagulation activation.

Original languageEnglish (US)
Pages (from-to)310-316
Number of pages7
JournalXenotransplantation
Volume22
Issue number4
DOIs
StatePublished - Jul 1 2015

Keywords

  • baboon
  • complement-regulatory protein
  • pig
  • xenograft rejection
  • xenotransplantation
  • α1 3-galactosyltransferase gene-knockout

ASJC Scopus subject areas

  • Immunology
  • Transplantation

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