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.
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.
Chen
Gang
G
Department of Surgery, University of Western Ontario, London, Ontario, Canada.
Sun
Hongtao
H
Yang
Hongji
H
Kubelik
Dalibor
D
Garcia
Bertha
B
Luo
Yigang
Y
Xiang
Ying
Y
Qian
Allen
A
Copeman
Laura
L
Liu
Weihua
W
Cardella
Carl J
CJ
Wang
Wanyu
W
Xiong
Yuliang
Y
Wall
William
W
White
David J
DJ
Zhong
Robert
R
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*
D000910:Antibodies, Heterophile; D014312:Trisaccharides; C076569:alpha-galactosyl epitope