title: Pig-to-baboon heterotopic heart transplantation--exploratory preliminary experience with pigs transgenic for human thrombomodulin and comparison of three costimulation blockade-based regimens.
abstract: BACKGROUND
  Three costimulation blockade-based regimens have been explored after transplantation of hearts from pigs of varying genetic backgrounds to determine whether CTLA4-Ig (abatacept) or anti-CD40mAb+CTLA4-Ig (belatacept) can successfully replace anti-CD154mAb.
  
  
  METHODS
  All pigs were on an α1,3-galactosyltransferase gene-knockout/CD46 transgenic (GTKO.CD46) background. Hearts transplanted into Group A baboons (n=4) expressed additional CD55, and those into Group B (n=3) expressed human thrombomodulin (TBM). Immunosuppression included anti-thymocyte globulin with anti-CD154mAb (Regimen 1: n=2) or abatacept (Regimen 2: n=2) or anti-CD40mAb+belatacept (Regimen 3: n=2). Regimens 1 and 2 included induction anti-CD20mAb and continuous heparin. One further baboon in Group B (B16311) received a modified Regimen 1. Baboons were followed by clinical/laboratory monitoring of immune/coagulation parameters. At biopsy, graft failure, or euthanasia, the graft was examined by microscopy.
  
  
  RESULTS
  Group A baboons survived 15 to 33 days, whereas Group B survived 52, 99, and 130 days, respectively. Thrombocytopenia and reduction in fibrinogen occurred within 21 days in Group A, suggesting thrombotic microangiopathy (TM), confirmed by histopathology. In Group B, with follow-up for >4 m, areas of myofiber degeneration and scarring were seen in two hearts at necropsy. A T-cell response was documented only in baboons receiving Regimen 2.
  
  
  CONCLUSIONS
  The combination of anti-CD40mAb+belatacept proved effective in preventing a T-cell response. The expression of TBM prevented thrombocytopenia and may possibly delay the development of TM and/or consumptive coagulopathy.
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.|Department of Surgery, Transplantation and Advanced Technologies, Vascular Surgery and Organ Transplant Unit, University Hospital of Catania, Catania, Italy.
authors.forename: Burcin
authors.initials: B
authors.lastname: Ekser
authors.affiliation: Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Vikas
authors.initials: V
authors.lastname: Satyananda
authors.affiliation: Department of Cardiothoracic Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Jay
authors.initials: J
authors.lastname: Bhama
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: Division of Laboratory Animal Resources, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Edwin
authors.initials: E
authors.lastname: Klein
authors.affiliation: Division of Laboratory Animal Resources, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Wagner
authors.affiliation: Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Cassandra
authors.initials: C
authors.lastname: Long
authors.affiliation: Department of Cardiothoracic Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Jnanesh
authors.initials: J
authors.lastname: Thacker
authors.affiliation: Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Jiang
authors.initials: J
authors.lastname: Li
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: Hao
authors.initials: H
authors.lastname: Zhou
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: Maolin
authors.initials: M
authors.lastname: Jiang
authors.affiliation: Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Santosh
authors.initials: S
authors.lastname: Nagaraju
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: Huidong
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Surgery, Transplantation and Advanced Technologies, Vascular Surgery and Organ Transplant Unit, University Hospital of Catania, Catania, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Veroux
authors.affiliation: Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Pietro
authors.initials: P
authors.lastname: Bajona
authors.affiliation: Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Wijkstrom
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: Revivicor, Blacksburg, VA, USA.
authors.forename: Carol
authors.initials: C
authors.lastname: Phelps
authors.affiliation: Gene Center, Ludwig Maximilians Universitat Munchen (LMU), Munich, Germany.
authors.forename: Nikolai
authors.initials: N
authors.lastname: Klymiuk
authors.affiliation: Gene Center, Ludwig Maximilians Universitat Munchen (LMU), Munich, Germany.
authors.forename: Eckhard
authors.initials: E
authors.lastname: Wolf
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: David K C
authors.initials: DK
authors.lastname: Cooper
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D006084:Graft Rejection / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology; D006321:Heart / Q000187:drug effects; D016027:Heart Transplantation / Q000379:methods; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D010215:Papio; D013552:Swine; D018180:Thrombomodulin / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D007166:Immunosuppressive Agents; D018180:Thrombomodulin
keywords: baboon; complement-regulatory proteins; costimulation blockade; heart; pig; thrombomodulin; thrombotic microangiopathy; xenotransplantation; α1,3-galactosyltransferase gene-knockout
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