title: The role of anti-non-Gal antibodies in the development of acute humoral xenograft rejection of hDAF transgenic porcine kidneys in baboons receiving anti-Gal antibody neutralization therapy.
abstract: BACKGROUND
  The present study was undertaken to determine the role of preformed and induced anti-non-Gal antibodies in the rejection of hDAF pig-to-baboon kidney xenotransplants after anti-Gal antibody neutralization therapy.
  
  
  METHODS
  Seven baboons received life-supporting kidney transplants from hDAF transgenic pigs. Anti-Gal antibodies were neutralized by GAS914 or TPC (a Gal PEG glycoconjugate polymer). Group 1 (n=5) underwent a conventional immunosuppressive therapy with FK506, rabbit anti-thymocyte serum/immunoglobulin, mycophenolate mofetil, and steroids. Group 2 (n=2) received an anti-humoral immunity regimen with LF15-0195, Rituxan and cobra venom factor in addition to ATG, FK506 and steroids. Levels of anti-non-Gal antibodies and their mediated complement-dependent cytotoxic activities (CDC) were detected by flow cytometry using Gal knockout (k/o) pig lymphocytes (LC) or endothelial cells (EC) as targets.
  
  
  RESULTS
  Continuous infusion of GAS914/TPC significantly reduced anti-Gal antibodies. In Group 1, four of five baboons developed severe acute humoral xenograft rejection (AHXR) and the rejection was associated with either a high level of preformed anti-non-Gal IgG or a marked elevation in induced anti-non-Gal IgG and IgM. Sera collected at the time of AHXR had a high level of CDC to porcine LC/EC from Gal k/o animals. The intensive anti-humoral therapy in Group 2 completely inhibited both anti-Gal and non-Gal antibody production and prevented AHXR. However, this therapy was not well tolerated by the baboons.
  
  
  CONCLUSIONS
  In a pig-to-baboon kidney transplant model, both preformed and induced anti-non-Gal antibodies are strongly associated with the pathogenesis of AHXR when anti-Gal antibodies are neutralized.
authors.affiliation: Department of Surgery, University of Western Ontario, London, Ontario, Canada.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Hongtao
authors.initials: H
authors.lastname: Sun
authors.forename: Hongji
authors.initials: H
authors.lastname: Yang
authors.forename: Dalibor
authors.initials: D
authors.lastname: Kubelik
authors.forename: Bertha
authors.initials: B
authors.lastname: Garcia
authors.forename: Yigang
authors.initials: Y
authors.lastname: Luo
authors.forename: Ying
authors.initials: Y
authors.lastname: Xiang
authors.forename: Allen
authors.initials: A
authors.lastname: Qian
authors.forename: Laura
authors.initials: L
authors.lastname: Copeman
authors.forename: Weihua
authors.initials: W
authors.lastname: Liu
authors.forename: Carl J
authors.initials: CJ
authors.lastname: Cardella
authors.forename: Wanyu
authors.initials: W
authors.lastname: Wang
authors.forename: Yuliang
authors.initials: Y
authors.lastname: Xiong
authors.forename: William
authors.initials: W
authors.lastname: Wall
authors.forename: David J
authors.initials: DJ
authors.lastname: White
authors.forename: Robert
authors.initials: R
authors.lastname: Zhong
mesh_terms: D000208:Acute Disease; D000818:Animals; D030801:Animals, Genetically Modified; D000910:Antibodies, Heterophile / Q000096:biosynthesis*; D006084:Graft Rejection / Q000209:etiology / Q000276:immunology*; D016030:Kidney Transplantation / Q000009:adverse effects / Q000276:immunology* / Q000473:pathology; D009500:Neutralization Tests; D010215:Papio; D034421:Sus scrofa; D014183:Transplantation, Heterologous; D014312:Trisaccharides / Q000276:immunology*
chemical_list: D000910:Antibodies, Heterophile; D014312:Trisaccharides; C076569:alpha-galactosyl epitope