A pig-to-mouse coronary artery transplantation model for investigating the pathogenicity of anti-pig antibody.
A pig-to-mouse coronary artery transplantation model for investigating the pathogenicity of anti-pig antibody.
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DOI：
10.1111/xen.12198
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发表时间：
2015-11
影响因子：
3.9
通讯作者：
McGregor, Christopher G. A.
中科院分区：
文献类型：
--
作者：
Lin, Yi;Miyagi, Naoto;Byrne, Guerard W.;Du, Zeji;Kogelberg, Heide;Gazi, Mozammel H.;Tazelaar, Henry D.;Wang, Chunsheng;McGregor, Christopher G. A.
关键词：
无半乳糖(GTKO)供体猪心脏移植排斥反应与血管非半乳糖抗体结合、内皮细胞损伤、活化和微血管血栓形成密切相关。我们采用猪到SCID/beige小动物移植模型，比较了狒狒抗体和人抗猪抗体的致病性。将野生型(GT+)或GTKO猪冠状动脉(PCAs)移植到SCID/beige小鼠的肾下主动脉内。移植后三天，受者输注抗猪抗体(抗SLA I类抗体、同型对照、未成熟或致敏的恒河猴血清或未成熟的人血清)。抗体注射后24 h取材，行组织学、免疫组织化学和原位杂交检测。在GT+和GTKO PCA受者中，注射抗SLA I抗体(但不是同型对照)后发生剂量依赖性的移植物内血栓形成。幼稚恒河猴血清诱导GT+移植物血栓形成。用Gal聚合物预处理原始狒狒血清可显著减少血栓形成，而将该血清注入GTKO PCA受体则未观察到血栓形成。未成熟的人血清可引起剂量依赖性的GTKO PCAs内血栓形成。在所有病例中，血栓形成涉及移植物特异性血管抗体和补体沉积、巨噬细胞黏附、EC分层和内皮下血栓形成。这项研究首次在活体内直接比较了幼稚的人和狒狒血清的致病性。结果表明，人类预制的非半乳糖抗体可能比狒狒具有更强的致病性。该模型显示的排斥移植物组织病理学类似于异种心脏移植中抗体介导的排斥反应，可用于评估单个蛋白质或碳水化合物特异性非半乳糖反应性抗体的致病性。
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. 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. 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. 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.
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