title: The innate immune response and activation of coagulation in alpha1,3-galactosyltransferase gene-knockout xenograft recipients.
abstract: BACKGROUND
  The role of the innate immune system in the development of thrombotic microangiopathy (TM) after alpha1,3-galactosyltransferase gene-knockout (GTKO) pig organ transplantation in primates is uncertain.
  
  
  METHODS
  Twelve organs (nine hearts, three kidneys) from GTKO pigs were transplanted into baboons that received no immunosuppressive therapy, partial regimens, or a full regimen based on costimulation blockade. After graft failure, histologic and immunohistologic examinations were carried out.
  
  
  RESULTS
  Graft survival of less than 1 day was prolonged to 2 to 12 days with partial regimens (acute humoral xenograft rejection) and to 5 and 8 weeks with the full regimen (TM). Clinical or laboratory features of consumptive coagulopathy occurred in 7 of 12 baboons. Immunohistochemistry demonstrated IgM, IgG, and complement deposition in most cases. Histopathology demonstrated neutrophil and macrophage infiltrates, intravascular fibrin deposition, and platelet aggregation (TM). Grafts showed expression of primate tissue factor (TF), with increased mRNA levels, and TF was also expressed on baboon macrophages/monocytes infiltrating the graft.
  
  
  CONCLUSIONS
  Our data suggest that (1) irrespective of the presence or absence of the adaptive immune response, early or late xenograft rejection is associated with activation of the innate immune system; and (2) porcine endothelial cell activation and primate TF expression by recipient innate immune cells may both contribute to the development of TM.
authors.affiliation: Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, PA 15261, USA.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Ezzelarab
authors.forename: Bertha
authors.initials: B
authors.lastname: Garcia
authors.forename: Agnes
authors.initials: A
authors.lastname: Azimzadeh
authors.forename: Hongtao
authors.initials: H
authors.lastname: Sun
authors.forename: Chih Che
authors.initials: CC
authors.lastname: Lin
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Hara
authors.forename: Sean
authors.initials: S
authors.lastname: Kelishadi
authors.forename: Tianshu
authors.initials: T
authors.lastname: Zhang
authors.forename: Yih Jyh
authors.initials: YJ
authors.lastname: Lin
authors.forename: Hao-Chi
authors.initials: HC
authors.lastname: Tai
authors.forename: Robert
authors.initials: R
authors.lastname: Wagner
authors.forename: Jnanesh
authors.initials: J
authors.lastname: Thacker
authors.forename: Noriko
authors.initials: N
authors.lastname: Murase
authors.forename: Kenneth
authors.initials: K
authors.lastname: McCurry
authors.forename: Rolf N
authors.initials: RN
authors.lastname: Barth
authors.forename: David
authors.initials: D
authors.lastname: Ayares
authors.forename: Richard N
authors.initials: RN
authors.lastname: Pierson
authors.forename: David K C
authors.initials: DK
authors.lastname: Cooper
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D005700:Galactosyltransferases / Q000172:deficiency* / Q000235:genetics*; D006085:Graft Survival / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D006720:Homozygote; D007113:Immunity, Innate; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000276:immunology* / Q000473:pathology; D010215:Papio; D013552:Swine / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D014183:Transplantation, Heterologous / Q000276:immunology*
chemical_list: D007166:Immunosuppressive Agents; D005700:Galactosyltransferases