Potential Antigens Involved in Delayed Xenograft Rejection in a Ggta1/Cmah Dko Pig-to-Monkey Model.
Potential Antigens Involved in Delayed Xenograft Rejection in a Ggta1/Cmah Dko Pig-to-Monkey Model.
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Ggta1/Cmah Dko 猪猴模型中延迟异种移植排斥相关的潜在抗原
DOI：
10.1038/s41598-017-10805-0
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发表时间：
2017-08-30
影响因子：
4.6
通讯作者：
Mou L
中科院分区：
文献类型：
--
作者：
Zhang J;Xie C;Lu Y;Zhou M;Qu Z;Yao D;Qiu C;Xu J;Pan D;Dai Y;Hara H;Cooper DKC;Ma S;Li M;Cai Z;Mou L
当通过删除猪体内的 Gal 表达来避免超急性排斥反应时，延迟异种移植排斥 (DXR) 成为成功异种移植的主要免疫障碍。本研究旨在调查 DXR 涉及的潜在抗原。我们从 GGTA1/CMAH 双敲除 (DKO) 猪（和 GGTA1-KO 猪）中分离出原代肾微血管内皮细胞 (RMEC) 和主动脉内皮细胞 (AEC)，并用这两种细胞免疫食蟹猴。致敏后，猴血清抗体与RMEC的结合和细胞毒性显着高于AEC(p<0.05)，表明RMEC比AEC具有更强的免疫原性。 GGTA1/CMAH DKO猪的转录组测序表明，RMEC中有1500个基因的表达量高于AEC，而896个基因的表达量低于AEC。接下来，我们选择了仅在猪 RMEC 中表达的 101 个候选基因，但在猪 AEC 或猴或人 RMEC 中不表达。当这些基因在 GGTA1/CMAH DKO RMEC 中单独敲除时，有 32 个基因与抗体结合减少相关，表明这些基因可能是 DXR 涉及的主要免疫靶点。这些基因可能是生产猪时删除的重要候选基因，猪肾异种移植物中针对这些基因的灵长类动物免疫反应降低。
When hyperacute rejection is avoided by deletion of Gal expression in the pig, delayed xenograft rejection (DXR) becomes a major immunologic barrier to successful xenotransplantation. This study was to investigate the potential antigens involved in DXR. We isolated primary renal microvascular endothelial cells (RMEC) and aortic endothelial cells (AEC) from a GGTA1/CMAH double-knockout (DKO) pig (and a GGTA1-KO pig) and immunized cynomolgus monkeys with both of these cells. After sensitization, monkey serum antibody binding and cytotoxicity to RMEC was significantly higher than to AEC(p < 0.05), suggesting that RMEC are more immunogenic than AEC. Transcriptome sequencing of GGTA1/CMAH DKO pigs indicated that the expression of 1,500 genes was higher in RMEC than in AEC, while expression of 896 genes was lower. Next, we selected 101 candidate genes expressed only in pig RMEC, but not in pig AEC or in monkey or human RMEC. When these genes were knocked out individually in GGTA1/CMAH DKO RMEC, 32 genes were associated with reduced antibody binding, indicating that these genes might be primary immunologic targets involved in DXR. These genes may be important candidates for deletion in producing pigs against which there is a reduced primate immune response in pig kidney xenograft.
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