A pig-to-mouse coronary artery transplantation model for investigating the pathogenicity of anti-pig antibody.

Abstract

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.

• Authors: Yi Lin, Naoto Miyagi, Guerard W Byrne, Zeji Du, Heide Kogelberg, Mozammel H Gazi, Henry D Tazelaar, Chunsheng Wang, Christopher G A McGregor
• Journal: Xenotransplantation (Xenotransplantation) 2015 Nov-Dec Vol. 22 Issue 6 Pg. 458-67 ISSN: 1399-3089 [Electronic] Denmark
• PMID: 26490445 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Chemical References

• Antibodies

Topics

• Animals
• Animals, Genetically Modified
• Antibodies (immunology)
• Coronary Vessels (transplantation)
• Graft Rejection (immunology)
• Graft Survival (immunology)
• Heterografts (transplantation)
• Humans
• Mice, SCID
• Papio (immunology)
• Swine
• Transplantation, Heterologous (methods)