Modified glycan models of pig-to-human xenotransplantation do not enhance the human-anti-pig T cell response
Modified glycan models of pig-to-human xenotransplantation do not enhance the human-anti-pig T cell response
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DOI：
10.1016/j.trim.2016.02.001
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发表时间：
2016-03-01
影响因子：
1.5
通讯作者：
Tector, A. Joseph
中科院分区：
文献类型：
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作者：
Butler, James R.;Wang, Zheng-Yu;Tector, A. Joseph
猪对人异种移植的转基因猪模型为解决可用实体器官日益短缺的问题提供了最直接的答案。最近发现了一种改良的猪聚糖模型，可以将人类抗体结合降低到与同种异体移植标准相当的水平。由于这一背景为急性体液异种移植排斥（AHXR）问题提供了答案，因此考虑这些修饰对细胞介导的排斥反应的影响非常重要。本研究的目的是检查目前相关的猪到人异种移植的聚糖敲除模型对淋巴细胞增殖测定的影响。为了实现这些目标，通过 CRISPR/Cas9 定向沉默 GGTA1 和 CMAH 基因培育出转基因猪。从这些动物中获得外周血单核细胞（PBMC）和脾细胞，并用作单向混合淋巴细胞反应中人类反应者的刺激源。在存在和不存在临床可用免疫调节剂的情况下测试反应。结论：临床相关的猪对人异种移植的聚糖敲除模型不会增强人抗猪细胞反应。目前可用的常规免疫抑制能够介导人类异种 T 细胞对这些敲除细胞的反应。 (C) 2016 Elsevier B.V. 保留所有权利。
Genetically modified porcine models of pig-to-human xenotransplantation offer the most immediate answer to a growing shortage of available solid organs. Recently a modified porcine glycan model has been discovered that reduces human antibody binding to levels comparable with allograft standards. As this background provides an answer to the problem of acute humoral xenograft rejection (AHXR), it is important to consider the impact these modifications have on measures of cell-mediated rejection. The objective of this study was to examine the impact of currently relevant glycan knockout models of pig-to-human xenotransplantation in a lymphocyte proliferation assay. To accomplish these goals, genetically modified pigs were created through CRISPR/Cas9-directed silencing of the GGTA1, and CMAH genes. Peripheral blood mononuclear cells (PBMCs) and spleen cells were obtained from these animals and used as a source of stimulation for human responders in one-way mixed lymphocyte reactions. The response was tested in the presence and absence of clinically available immunomodifiers. Conclusions: Clinically relevant glycan knockout models of pig-to-human xenotransplantation do not enhance the human anti-pig cellular response. Currently available and conventional immunosuppression has the capacity to mediate the human xenogeneic T cell response to these knockout cells. (C) 2016 Elsevier B.V. All rights reserved.