在猪动脉组织移植的人源化小鼠模型中模拟人抗猪异种免疫反应。

IF 3.3 4区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Xenotransplantation Pub Date : 2023-09-01 Epub Date: 2023-09-11 DOI:10.1111/xen.12824
Minghui Fang, Jun Zou, Fei Xu, Xue Wang, Shucheng Hua, Qi Zhou, Yong-Guang Yang, Zheng Hu
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引用次数: 0

摘要

背景:表面含有内皮细胞的血管与宿主血液直接接触,是异种移植物排斥反应的第一个靶点。目前,我们对人类抗猪血管免疫反应的理解主要基于使用猪内皮细胞的体外测定。因此,有必要开发一种允许在体内研究人类对猪血管的免疫排斥反应的动物模型。方法:将猪动脉组织(PAT)移植到人免疫系统(HIS)小鼠或免疫缺陷NSG小鼠(作为对照)中。使用组织学和免疫组织化学对移植物内人类免疫细胞浸润和抗体沉积进行定量。使用混合淋巴细胞反应和补体依赖性杀伤测定法对供体抗原特异性免疫应答进行定量。结果:在来自免疫缺陷NSG小鼠的PAT异种移植物中检测到猪CD31+EC,并且从第3周到第5周增加了2倍。然而,与NSG小鼠相比,HIS小鼠中的PAT异种移植物具有显著较低的猪CD31+EC数量,并且从第3周到第5周显示出显著减少。HIS小鼠的PAT异种移植物排斥反应与人类免疫细胞的密集浸润、人类IgM和IgG抗体的沉积以及三级淋巴结构的形成有关。在PAT移植的HIS小鼠中检测到强大的供体猪抗原特异性人T细胞和抗体反应。结论:我们建立了一种人源化小鼠模型,通过体内PAT移植来评估人类抗猪异种免疫反应。该模型有望促进猪基因编辑策略(EC表面表达)的完善和临床猪器官异种移植局部免疫抑制策略的测试。
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Modeling human anti-pig xenoimmune responses in a pig artery tissue grafted humanized mouse model.

Background: Blood vessels that contain endothelial cells (ECs) on the surface are in direct contact with host blood and are the first target of xenograft rejection. Currently, our understanding of human anti-pig vessel immune responses is primarily based on in vitro assays using pig ECs. Therefore, it is necessary to develop an animal model that permits in vivo study of human immunological rejection of pig vessels.

Methods: Pig artery tissues (PAT) were transplanted into human immune system (HIS) mice or immunodeficient NSG mice (as controls). Intragraft human immune cell infiltration and antibody deposition were quantified using histology and immunohistochemistry. Donor antigen-specific immune responses were quantified using a mixed lymphocyte reaction and a complement-dependent killing assay.

Results: Pig CD31+ ECs were detected and increased 2-fold from weeks 3 to 5 in PAT xenografts from immunodeficient NSG mice. However, compared with NSG mice, PAT xenografts in HIS mice had significantly lower numbers of porcine CD31+ ECs and showed a marked reduction from week 3 to week 5. PAT xenograft rejection in HIS mice is associated with intensive infiltration of human immune cells, deposition of human IgM and IgG antibodies, and the formation of a tertiary lymphoid structure. Robust donor pig antigen-specific human T cells and antibody responses were detected in PAT-transplanted HIS mice.

Conclusion: We have developed a humanized mouse model to evaluate human anti-pig xenoimmune responses by PAT transplantation in vivo. This model is expected to facilitate the refinement of pig gene-editing strategies (the expression on EC surface) and the testing of local immunosuppressive strategies for clinical pig organ xenotransplantation.

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来源期刊
Xenotransplantation
Xenotransplantation 医学-医学:研究与实验
CiteScore
6.80
自引率
15.40%
发文量
58
审稿时长
>12 weeks
期刊介绍: Xenotransplantation provides its readership with rapid communication of new findings in the field of organ and tissue transplantation across species barriers.The journal is not only of interest to those whose primary area is xenotransplantation, but also to veterinarians, microbiologists and geneticists. It also investigates and reports on the controversial theological, ethical, legal and psychological implications of xenotransplantation.
期刊最新文献
Ethical Implications of Social Science Research on Xenotransplantation. ECG Features in Orthotopic Cardiac Xenotransplantation: Comparisons With Published Literature. Ultrasound Assessment of Pleural Effusions After Orthotopic Pig-to-Baboon Cardiac Xenotransplantation. Xenotransplantation Literature Update December 2023–June 2024 Hendrik Jan (Henk) Schuurman, MSc, PhD (1950-2024): In Memoriam.
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