A pig-to-mouse coronary artery transplantation model for investigating the pathogenicity of anti-pig antibody.
BACKGROUND
Rejection of Gal-free (GTKO) donor pig cardiac xenografts is strongly associated with vascular non-Gal antibody binding, endothelial cell (EC) injury, and activation and microvascular thrombosis. We adopted a pig-to-SCID/beige small animal transplant model to compare the pathogenicity of baboon and human anti-pig antibody.


METHODS
Wild-type (GT(+) ) or GTKO porcine coronary arteries (PCAs) were transplanted into the infrarenal aorta of SCID/beige mice. Three days after transplant, recipients were infused with anti-pig antibody (anti-SLA class I, an isotype control, naive or sensitized baboon serum, or naive human serum). PCAs were recovered 24 h after antibody infusion and examined using histology, immunohistochemistry, and in situ hybridization.


RESULTS
Dose-dependent intragraft thrombosis occurred after infusion of anti-SLA I antibody (but not isotype control) in GT(+) and GTKO PCA recipients. Naive baboon serum induced thrombosis in GT(+) grafts. Thrombosis was significantly reduced by pre-treating naive baboon serum with Gal polymer and not observed when this serum was infused to GTKO PCA recipients. Naive human serum caused dose-dependent intragraft thrombosis of GTKO PCAs. In all cases, thrombosis involved graft-specific vascular antibody and complement deposition, macrophage adherence, EC delamination, and subendothelial thrombus formation.


CONCLUSIONS
This study provides the first direct in vivo comparison of the pathogenicity of naive human and baboon serum. The results suggest that human preformed non-Gal antibody may have increased pathogenicity compared to baboon. This model, which showed a rejected graft histopathology similar to antibody-mediated rejection in cardiac xenotransplantation, may be useful to assess the pathogenicity of individual protein or carbohydrate specific non-Gal reactive antibodies.
Department of Surgery, Mayo Clinic, Rochester, MN, USA.|Department of Cardiovascular Surgery, Zhongshan Hospital of Fudan University, Shanghai, China.
Yi
Y
Lin
Department of Surgery, Mayo Clinic, Rochester, MN, USA.
Naoto
N
Miyagi
Department of Surgery, Mayo Clinic, Rochester, MN, USA.|Institute of Cardiovascular Science, University College London, London, UK.
Guerard W
GW
Byrne
Department of Surgery, Mayo Clinic, Rochester, MN, USA.
Zeji
Z
Du
Institute of Cardiovascular Science, University College London, London, UK.
Heide
H
Kogelberg
Department of Surgery, Mayo Clinic, Rochester, MN, USA.
Mozammel H
MH
Gazi
Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, AZ, USA.
Henry D
HD
Tazelaar
Department of Cardiovascular Surgery, Zhongshan Hospital of Fudan University, Shanghai, China.
Chunsheng
C
Wang
Department of Surgery, Mayo Clinic, Rochester, MN, USA.|Institute of Cardiovascular Science, University College London, London, UK.
Christopher G A
CG
McGregor
D000818:Animals; D030801:Animals, Genetically Modified; D000906:Antibodies / Q000276:immunology*; D003331:Coronary Vessels / Q000637:transplantation*; D006084:Graft Rejection / Q000276:immunology*; D006085:Graft Survival / Q000276:immunology; D064593:Heterografts / Q000637:transplantation*; D006801:Humans; D016513:Mice, SCID; D010215:Papio / Q000276:immunology*; D013552:Swine; D014183:Transplantation, Heterologous / Q000379:methods
D000906:Antibodies
anti-pig antibody; coronary artery transplantation; delayed xenograft rejection; pig-to-mouse chimera; small animal transplantation model