title: Early graft failure of GalTKO pig organs in baboons is reduced by expression of a human complement pathway-regulatory protein.
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.
authors.affiliation: University of Maryland School of Medicine and Baltimore VAMC, Baltimore, MD, USA.
authors.forename: Agnes M
authors.initials: AM
authors.lastname: Azimzadeh
authors.affiliation: University of Maryland School of Medicine and Baltimore VAMC, Baltimore, MD, USA.
authors.forename: Sean S
authors.initials: SS
authors.lastname: Kelishadi
authors.affiliation: Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Mohamed B
authors.initials: MB
authors.lastname: Ezzelarab
authors.affiliation: Cardiothoracic Surgery Research Program, NHLBI/NIH, Bethesda, MD, USA.
authors.forename: Avneesh K
authors.initials: AK
authors.lastname: Singh
authors.affiliation: University of Maryland School of Medicine and Baltimore VAMC, Baltimore, MD, USA.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Stoddard
authors.affiliation: Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Hayato
authors.initials: H
authors.lastname: Iwase
authors.affiliation: University of Maryland School of Medicine and Baltimore VAMC, Baltimore, MD, USA.
authors.forename: Tianshu
authors.initials: T
authors.lastname: Zhang
authors.affiliation: University of Maryland School of Medicine and Baltimore VAMC, Baltimore, MD, USA.
authors.forename: Lars
authors.initials: L
authors.lastname: Burdorf
authors.affiliation: University of Maryland School of Medicine and Baltimore VAMC, Baltimore, MD, USA.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Sievert
authors.affiliation: University of Maryland School of Medicine and Baltimore VAMC, Baltimore, MD, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Avon
authors.affiliation: University of Maryland School of Medicine and Baltimore VAMC, Baltimore, MD, USA.
authors.forename: Xiangfei
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Revivicor, Blacksburg, VA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Ayares
authors.affiliation: Cardiothoracic Surgery Research Program, NHLBI/NIH, Bethesda, MD, USA.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Horvath
authors.affiliation: Cardiothoracic Surgery Research Program, NHLBI/NIH, Bethesda, MD, USA.
authors.forename: Philip C
authors.initials: PC
authors.lastname: Corcoran
authors.affiliation: Cardiothoracic Surgery Research Program, NHLBI/NIH, Bethesda, MD, USA.
authors.forename: Muhammad M
authors.initials: MM
authors.lastname: Mohiuddin
authors.affiliation: University of Maryland School of Medicine and Baltimore VAMC, Baltimore, MD, USA.
authors.forename: Rolf N
authors.initials: RN
authors.lastname: Barth
authors.affiliation: Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: David K C
authors.initials: DK
authors.lastname: Cooper
authors.affiliation: University of Maryland School of Medicine and Baltimore VAMC, Baltimore, MD, USA.
authors.forename: Richard N
authors.initials: RN
authors.lastname: Pierson
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D018958:CD55 Antigens / Q000235:genetics / Q000276:immunology*; D003167:Complement Activation; D004187:Disaccharides / Q000276:immunology; D005700:Galactosyltransferases / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D055786:Gene Knockout Techniques; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000276:immunology; D016027:Heart Transplantation / Q000009:adverse effects / Q000379:methods; D006801:Humans; D016030:Kidney Transplantation / Q000009:adverse effects / Q000379:methods; D051916:Membrane Cofactor Protein / Q000235:genetics / Q000276:immunology*; D010215:Papio; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology; D013552:Swine; D014183:Transplantation, Heterologous / Q000009:adverse effects / Q000379:methods*
chemical_list: C497857:CD46 protein, human; D018958:CD55 Antigens; D004187:Disaccharides; D051916:Membrane Cofactor Protein; D011994:Recombinant Proteins; C055075:galactosyl-(1-3)galactose; D005700:Galactosyltransferases; C530267:alpha-1,3-galactosyltransferase 1, porcine
keywords: baboon; complement-regulatory protein; pig; xenograft rejection; xenotransplantation; α1, 3-galactosyltransferase gene-knockout