Xenotransplantation · 2015
A pig-to-mouse coronary artery transplantation model for investigating the pathogenicity of anti-pig antibody.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Lin Yi, Miyagi Naoto, Byrne Guerard W, Du Zeji, Kogelberg Heide, Gazi Mozammel H, Tazelaar Henry D, Wang Chunsheng, McGregor Christopher G A
Аннотация
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.
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.