title: Immunological and physiological observations in baboons with life-supporting genetically engineered pig kidney grafts.
abstract: Genetically engineered pigs could provide a source of kidneys for clinical transplantation. The two longest kidney graft survivals reported to date have been 136 and 310 days, but graft survival >30 days has been unusual until recently.
  
  
  
  Donor pigs (n=4) were on an α1,3-galactosyltransferase gene-knockout (GTKO)/human complement regulatory protein (CD46) background (GTKO/CD46). In addition, the pigs were transgenic for at least one human coagulation regulatory protein. Two baboons received a kidney from a six-gene pig (GroupA) and two from a three-gene pig (GroupB). Immunosuppressive therapy was identical in all four cases and consisted of anti-thymoglobulin (ATG)+anti-CD20mAb (induction) and anti-CD40mAb+rapamycin+corticosteroids (maintenance). Anti-TNF-α and anti-IL-6R mAbs were administered to reduce the inflammatory response. Baboons were followed by clinical/laboratory monitoring of immune/coagulation/inflammatory/physiological parameters. At biopsy or euthanasia, the grafts were examined by microscopy.
  
  
  
  The two GroupA baboons remained healthy with normal renal function >7 and >8 months, respectively, but then developed infectious complications. However, no features of a consumptive coagulopathy, eg, thrombocytopenia and reduction of fibrinogen, or of a protein-losing nephropathy were observed. There was no evidence of an elicited anti-pig antibody response, and histology of biopsies taken at approximately 4, 6, and 7 months and at necropsy showed no significant abnormalities. In contrast, both GroupB baboons developed features of a consumptive coagulopathy and required euthanasia on day 12.
  
  
  
  The combination of (i) a graft from a specific six-gene genetically modified pig, (ii) an effective immunosuppressive regimen, and (iii) anti-inflammatory therapy prevented immune injury, a protein-losing nephropathy, and coagulation dysfunction for >7 months. Although the number of experiments is very limited, our impression is that expression of human endothelial protein C receptor (±CD55) in the graft is important if coagulation dysregulation is to be avoided.
authors.affiliation: Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Hayato
authors.initials: H
authors.lastname: Iwase
authors.affiliation: Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Hara
authors.affiliation: Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Ezzelarab
authors.affiliation: Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA.|Center for Kidney Transplantation, Second Affiliated Hospital of the University of South China, Hengyang, Hunan, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Li
authors.affiliation: Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA.|Department of General Surgery, Second Xiangya Hospital of the Central South University, Changsha, Hunan, China.
authors.forename: Zhongqiang
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA.|Center for Kidney Transplantation, Second Affiliated Hospital of the University of South China, Hengyang, Hunan, China.
authors.forename: Bingsi
authors.initials: B
authors.lastname: Gao
authors.affiliation: Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA.|Department of General Surgery, First Hospital of Shanxi Medical University, Taiyuan, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.affiliation: Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Cassandra
authors.initials: C
authors.lastname: Long
authors.affiliation: Center for Kidney Transplantation, Second Affiliated Hospital of the University of South China, Hengyang, Hunan, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Division of Laboratory Animal Resources, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Cassano
authors.affiliation: Division of Laboratory Animal Resources, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Edwin
authors.initials: E
authors.lastname: Klein
authors.affiliation: Revivicor, Blacksburg, VA, USA.
authors.forename: Carol
authors.initials: C
authors.lastname: Phelps
authors.affiliation: Revivicor, Blacksburg, VA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Ayares
authors.affiliation: Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Abhinav
authors.initials: A
authors.lastname: Humar
authors.affiliation: Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Wijkstrom
authors.affiliation: Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: David K C
authors.identifier: 0000-0002-8899-9431
authors.initials: DKC
authors.lastname: Cooper
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology*; D006085:Graft Survival / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D007668:Kidney / Q000276:immunology / Q000601:surgery*; D016030:Kidney Transplantation / Q000379:methods; D010215:Papio; D013552:Swine; D014183:Transplantation, Heterologous / Q000379:methods; D019737:Transplants / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D007166:Immunosuppressive Agents; D014409:Tumor Necrosis Factor-alpha
keywords: anti-IL-6R antagonist; costimulation blockade; genetically engineered; kidney; pig; xenotransplantation