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多基因编辑猪-猴心脏、肝脏、肾脏移植临床前研究初步报道

张玄 王琳 张洪涛 杨诏旭 岳树强 杨雁灵 董海龙 陈敏 路志红 程亮 刘金成 俞世强 张更 秦卫军 李纪鹏 魏红江 杨璐菡 周亮 龙恩武 陶开山 窦科峰

张玄, 王琳, 张洪涛, 等. 多基因编辑猪-猴心脏、肝脏、肾脏移植临床前研究初步报道[J]. 器官移植, 2021, 12(1): 51-56. doi: 10.3969/j.issn.1674-7445.2021.01.008
引用本文: 张玄, 王琳, 张洪涛, 等. 多基因编辑猪-猴心脏、肝脏、肾脏移植临床前研究初步报道[J]. 器官移植, 2021, 12(1): 51-56. doi: 10.3969/j.issn.1674-7445.2021.01.008
Zhang Xuan, Wang Lin, Zhang Hongtao, et al. Preliminary report of preclinical trial of multi-genome engineering pig-to-macaque heart, liver and kidney transplantation[J]. ORGAN TRANSPLANTATION, 2021, 12(1): 51-56. doi: 10.3969/j.issn.1674-7445.2021.01.008
Citation: Zhang Xuan, Wang Lin, Zhang Hongtao, et al. Preliminary report of preclinical trial of multi-genome engineering pig-to-macaque heart, liver and kidney transplantation[J]. ORGAN TRANSPLANTATION, 2021, 12(1): 51-56. doi: 10.3969/j.issn.1674-7445.2021.01.008

多基因编辑猪-猴心脏、肝脏、肾脏移植临床前研究初步报道

doi: 10.3969/j.issn.1674-7445.2021.01.008
基金项目: 

国家“973计划”项目 2015CB554100

国家重点研发计划项目 2017YFC1103703

详细信息
    通讯作者:

    陶开山,主任医师,教授,博士研究生导师,Email: taokaishan0686@163.com

    窦科峰,主任医师,教授,博士研究生导师,Email:doukef@fmmu.edu.cn

  • 中图分类号: R617, Q78

Preliminary report of preclinical trial of multi-genome engineering pig-to-macaque heart, liver and kidney transplantation

More Information
  • 摘要:   目的  探讨目前国际上基因改造程度最大的基因编辑猪在临床前异种器官移植中的应用前景。  方法  将1只猪内源性逆转录病毒(PERV)敲除联合3种主要异种抗原基因敲除以及抑制补体活化、调节凝血紊乱、抗炎抗吞噬的9种人源化基因转入猪(PERV-KO/3-KO/9-TG)作为供体,获取其心脏、肝脏和肾脏,分别移植给3只恒河猴受体,建立猪-猴异种器官移植临床前研究模型。观察血流重建后各移植物的功能状态并总结受体存活情况;监测移植物的血流动力学情况;比较各器官移植受体的血液学指标变化;观察移植物组织病理学表现。  结果  血流重建后各移植器官颜色红润、质地柔软、血流灌注状态良好。术后1 d,移植心脏、肝脏和肾脏均表现为动、静脉血流状态充盈,灌注情况良好。心脏、肝脏和肾脏移植受体的术后存活时间分别为7 d、26 d和1 d。心脏移植受体术后1 d肌酸激酶、肌酸激酶同工酶以及乳酸脱氢酶水平均升高,至术后6 d逐渐恢复至接近正常水平。术后7 d各项指标均急剧升高。肝脏移植受体术后2 d天冬氨酸转氨酶水平升高,术后10 d转氨酶基本恢复正常,但总胆红素持续升高。术后12 d天冬氨酸转氨酶和丙氨酸转氨酶水平均出现升高,至术后15 d达到高峰。肾脏移植受体术后1 d出现轻微蛋白尿,后因突发严重心律失常死亡。组织病理学显示心脏和肾脏移植物组织结构接近正常,移植肝脏表现为片状坏死,肝组织结构出现紊乱,并伴有炎症损伤、间质出血和血栓性微血管病形成。  结论  PERV-KO/3-KO/9-TG猪在克服超急性排斥反应、缓解体液性排斥反应及凝血紊乱方面具有一定优势,但其能否作为临床异种器官移植潜在供体需进一步评估。

     

  • 图  1  血流重建后各移植物的功能状态

    注:A、B图示心脏移植受体及移植心脏;C、D图示肝脏移植受体及移植肝脏;E、F图示肾脏移植受体及移植肾脏。

    Figure  1.  The functional states of xenografts after blood flow reconstruction

    图  2  术后1 d各移植物的血流动力学情况

    注:A、B、C图分别示心脏、肝脏、肾脏移植术后移植物的血流动力学情况。

    Figure  2.  Hemodynamic condition of xenografts at 1 d after operation

    图  3  心脏移植和肝脏移植受体心肌酶谱和肝功能的变化

    注:A图示心脏移植受体心肌酶谱的变化;B图示肝脏移植受体肝功能的变化。

    Figure  3.  Changes of myocardial enzyme spectrum and liver function of heart transplant and liver transplant recipients

    图  4  各移植物组织病理学表现(苏木素-伊红,×200)

    注:A图示移植心脏组织;B、C图示移植肝脏组织;D图示移植肾脏组织。

    Figure  4.  Histopathological manifestations of xenografts

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出版历程
  • 收稿日期:  2020-12-17
  • 网络出版日期:  2021-01-19
  • 刊出日期:  2021-01-19

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