异种肝移植的探索之路：从科学研究走向临床应用

李霄; 曹薇薇; 余良

doi:10.3969/j.issn.1674-7445.2024043

异种肝移植的探索之路：从科学研究走向临床应用

doi: 10.3969/j.issn.1674-7445.2024043

李霄^1, ,,
曹薇薇²,
余良³

11.
710032　西安，空军军医大学西京医院综合外科综合外科
22.
检验科
33.
信息科

基金项目: 国家自然科学基金（82070681、81970566）；陕西省重点研发计划资助项目（2023-YBSF-429）；陕西省自然科学基础研究计划资助项目（2022JM-537）

详细信息

通讯作者:
李霄（ORCID 0000-0003-1731-7488），Email: lixiao0757@163.com

中图分类号: R617, Q78
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- 文章访问数: 75
- HTML全文浏览量: 38
- PDF下载量: 4
- 被引次数: 0
出版历程
- 收稿日期: 2024-02-01
- 网络出版日期: 2024-04-28

Exploratory road of liver xenotransplantation: from scientific research to clinical application

Li Xiao^{1
, ,},
Cao Weiwei²,
Yu Liang³

11.
Department of General Surgery, Xijing Hospital, the Air Force Military Medical University, Xi’an 710032, China

More Information

Corresponding author: Li Xiao, Email: lixiao0757@163.com

摘要

摘要: 随着手术技术进步及围手术期管理水平提升，器官移植受者及移植物存活率显著提高，供器官短缺已成为限制器官移植进一步发展的主要障碍。近期，以基因修饰猪为供体的异种肾移植和异种心脏移植已进入临床试验并取得了不错的效果，异种移植再一次成为生物医学研究的热点。与心脏和肾脏相比，基因修饰猪的肝脏在非人灵长类动物体内的存活时间还比较短，且实验结果差异性较大，尚不具备进入临床试验的条件。因此，本文从术式选择、凝血功能障碍和急性血管性排斥反应3个方面，总结目前异种肝移植的研究进展，讨论阻碍异种肝移植进入临床试验的主要问题及可能的解决策略，以期为异种肝移植从科学研究走向临床提供参考。
- 异种移植 /
- 肝移植 /
- 供者短缺 /
- 基因修饰猪 /
- 全肝移植 /
- 辅助性肝移植 /
- 凝血功能障碍 /
- 急性血管性排斥反应
Abstract: With the advancement of surgical technologies and the improvement of perioperative management, the survival rates of organ transplant recipients and grafts have been significantly elevated. Shortage of donor organs has become the main obstacle to further development of organ transplantation. Recently, kidney and heart xenotransplantation with genetically modified pigs as donors have entered clinical trials and achieved favorable results. Xenotransplantation has repeatedly become a hot spot in biomedical research. Compared with heart and kidney, the survival time of liver grafts from genetically modified pigs in non-human primates is shorter. Besides, experimental results are dramatically different. Hence, it is not eligible for clinical trials. Consequently, recent research progress in xenotransplantation was reviewed from surgical pattern selection, coagulation dysfunction and acute vascular rejection, advances in liver xenotransplantation were summarized, and the main problems hindering xenotransplantation from entering clinical trials and potential solutions were illustrated, aiming to provide reference for xenotransplantation from scientific research to clinical application.
- Xenotransplantation /
- Liver transplantation /
- Donor shortage /
- Genetically modified pig /
- Whole liver transplantation /
- Auxiliary liver transplantation /
- Coagulation disorder /
- Acute vascular rejection

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参考文献(38)

[1]	ANDERSON DJ, LOCKE JE. Progress towards solving the donor organ shortage[J]. Nat Rev Nephrol, 2023, 19(2): 83-84. DOI: 10.1038/s41581-022-00664-y.
[2]	JOHNSTON-WEBBER C, MAH J, PRIONAS A, et al. Solid organ donation and transplantation in the United Kingdom: good governance is key to success[J]. Transpl Int, 2023, 36: 11012. DOI: 10.3389/ti.2023.11012.
[3]	窦科峰, 张玄, 杨志鹏. 中国肝移植的发展与挑战[J]. 中华外科杂志, 2024, 62(1): 1-5. DOI: 10.3760/cma.j.cn112139-20231030-00202. DOU KF, ZHANG X, YANG ZP. Developments and challenges of liver transplantation in China[J]. Chin J Surg, 2024, 62(1): 1-5. DOI: 10.3760/cma.j.cn112139-20231030-00202.
[4]	SYKES M. Developing pig-to-human organ transplants[J]. Science, 2022, 378(6616): 135-136. DOI: 10.1126/science.abo7935.
[5]	许艺红, 肖义军. 猪作为人类器官移植供体的研究进展[J]. 生物学通报, 2022, 57(11): 1-4. DOI: 10.3969/j.issn.0006-3193.2022.11.001. XU YH, XIAO YJ. Research progress on pigs as human organ transplant donors[J]. Bull Biol, 2022, 57(11): 1-4. DOI: 10.3969/j.issn.0006-3193.2022.11.001.
[6]	李霄, 窦科峰. 突破供肝短缺难题: 异种肝移植的发展与创新[J]. 临床肝胆病杂志, 2022, 38(10): 2201-2205. DOI: 10.3969/j.issn.1001-5256.2022.10.001. LI X, DOU KF. Development and progress of liver xenotransplantation: a potential breakthrough for current shortage of donor liver[J]. J Clin Hepatol, 2022, 38(10): 2201-2205. DOI: 10.3969/j.issn.1001-5256.2022.10.001.
[7]	SINGH AK, GRIFFITH BP, GOERLICH CE, et al. The road to the first FDA-approved genetically engineered pig heart transplantation into human[J]. Xenotransplantation, 2022, 29(5): e12776. DOI: 10.1111/xen.12776.
[8]	CARVALHO T. Two US surgical teams transplant functional pig kidneys into humans in xenotransplantation success[J]. Nat Med, 2023, 29(11): 2671-2672. DOI: 10.1038/d41591-023-00078-8.
[9]	LEE KW, PARK SSW, KIM DS, et al. Auxiliary liver xenotransplantation technique in a transgenic pig-to-non-human primate model: a surgical approach to prolong survival[J]. Xenotransplantation, 2023, 30(5): e12814. DOI: 10.1111/xen.12814.
[10]	EKSER B, LONG C, ECHEVERRI GJ, et al. Impact of thrombocytopenia on survival of baboons with genetically modified pig liver transplants: clinical relevance[J]. Am J Transplant, 2010, 10(2): 273-285. DOI: 10.1111/j.1600-6143.2009.02945.x.
[11]	KIM K, SCHUETZ C, ELIAS N, et al. Up to 9-day survival and control of thrombocytopenia following alpha1, 3-galactosyl transferase knockout swine liver xenotransplantation in baboons[J]. Xenotransplantation, 2012, 19(4): 256-264. DOI: 10.1111/j.1399-3089.2012.00717.x.
[12]	NAVARRO-ALVAREZ N, SHAH JA, ZHU A, et al. The effects of exogenous administration of human coagulation factors following pig-to-baboon liver xenotransplantation[J]. Am J Transplant, 2016, 16(6): 1715-1725. DOI: 10.1111/ajt.13647.
[13]	SHAH JA, NAVARRO-ALVAREZ N, DEFAZIO M, et al. A bridge to somewhere: 25-day survival after pig-to-baboon liver xenotransplantation[J]. Ann Surg, 2016, 263(6): 1069-1071. DOI: 10.1097/SLA.00000000000 01659.
[14]	SHAH JA, PATEL MS, ELIAS N, et al. Prolonged survival following pig-to-primate liver xenotransplantation utilizing exogenous coagulation factors and costimulation blockade[J]. Am J Transplant, 2017, 17(8): 2178-2185. DOI: 10.1111/ajt.14341.
[15]	YEH H, MACHAIDZE Z, WAMALA I, et al. Increased transfusion-free survival following auxiliary pig liver xenotransplantation[J]. Xenotransplantation, 2014, 21(5): 454-464. DOI: 10.1111/xen.12111.
[16]	JI H, LI X, YUE S, et al. Pig BMSCs transfected with human TFPI combat species incompatibility and regulate the human TF pathway in vitro and in a rodent model[J]. Cell Physiol Biochem, 2015, 36(1): 233-249. DOI: 10.1159/000374067.
[17]	ZHANG X, COOPER DKC, DOU K. Genetically-engineered pig-to-human organ transplantation: a new beginning[J]. Sci Bull (Beijing), 2022, 67(18): 1827-1829. DOI: 10.1016/j.scib.2022.08.026.
[18]	LAMM V, EKSER B, VAGEFI PA, et al. Bridging to allotransplantation-is pig liver xenotransplantation the best option?[J]. Transplantation, 2022, 106(1): 26-36. DOI: 10.1097/TP.0000000000003722.
[19]	李霄, 陶开山. 异种肝移植手术的特点与难点[J]. 临床肝胆病杂志, 2022, 38(10): 2206-2209. DOI: 10.3969/j.issn.1001-5256.2022.10.002. LI X, TAO KS. Liver xenotransplantation techniques: characteristics and difficulties[J]. J Clin Hepatol, 2022, 38(10): 2206-2209. DOI: 10.3969/j.issn.1001-5256.2022.10.002.
[20]	CROSS-NAJAFI AA, LOPEZ K, ISIDAN A, et al. Current barriers to clinical liver xenotransplantation[J]. Front Immunol, 2022, 13: 827535. DOI: 10.3389/fimmu.2022.827535.
[21]	CONNOLLY MR, KURAVI K, BURDORF L, et al. Humanized von Willebrand factor reduces platelet sequestration in ex vivo and in vivo xenotransplant models[J]. Xenotransplantation, 2021, 28(6): e12712. DOI: 10.1111/xen.12712.
[22]	ZHOU Q, LI T, WANG K, et al. Current status of xenotransplantation research and the strategies for preventing xenograft rejection[J]. Front Immunol, 2022, 13: 928173. DOI: 10.3389/fimmu.2022.928173.
[23]	LI T, LV Y, SUN R, et al. Incompatibility between recipient CD47 and donor SIRPα is not a key risk factor for thrombocytopenia or anemia following rat liver xenotransplantation in mice[J]. Xenotransplantation, 2021, 28(3): e12657. DOI: 10.1111/xen.12657.
[24]	MAEDA A, KOGATA S, TOYAMA C, et al. The innate cellular immune response in xenotransplantation[J]. Front Immunol, 2022, 13: 858604. DOI: 10.3389/fimmu.2022.858604.
[25]	ZHANG X, LI X, YANG Z, et al. A review of pig liver xenotransplantation: current problems and recent progress[J]. Xenotransplantation, 2019, 26(3): e12497. DOI: 10.1111/xen.12497.
[26]	SAMY KP, BUTLER JR, LI P, et al. The role of costimulation blockade in solid organ and islet xenotransplantation[J]. J Immunol Res, 2017: 8415205. DOI: 10.1155/2017/8415205.
[27]	GRACIA-SANCHO J, CAPARRÓS E, FERNÁNDEZ-IGLESIAS A, et al. Role of liver sinusoidal endothelial cells in liver diseases[J]. Nat Rev Gastroenterol Hepatol, 2021, 18(6): 411-431. DOI: 10.1038/s41575-020-00411-3.
[28]	MCCONNELL MJ, KOSTALLARI E, IBRAHIM SH, et al. The evolving role of liver sinusoidal endothelial cells in liver health and disease[J]. Hepatology, 2023, 78(2): 649-669. DOI: 10.1097/HEP.0000000000000207.
[29]	PARIS LL, CHIHARA RK, REYES LM, et al. ASGR1 expressed by porcine enriched liver sinusoidal endothelial cells mediates human platelet phagocytosis in vitro[J]. Xenotransplantation, 2011, 18(4): 245-51. DOI: 10.1111/j.1399-3089.2011.00639.x.
[30]	KOBAYASHI H, MATSUBARA S, IMANAKA S. The role of tissue factor pathway inhibitor 2 in the coagulation and fibrinolysis system[J]. J Obstet Gynaecol Res, 2023, 49(7): 1677-1683. DOI: 10.1111/jog.15660.
[31]	MAST AE, RUF W. Regulation of coagulation by tissue factor pathway inhibitor: implications for hemophilia therapy[J]. J Thromb Haemost, 2022, 20(6): 1290-1300. DOI: 10.1111/jth.15697.
[32]	WITTIG J, DREKOLIA MK, KYSELOVA A, et al. Endothelial-dependent S-Sulfhydration of tissue factor pathway inhibitor regulates blood coagulation[J]. Redox Biol, 2023, 62: 102694. DOI: 10.1016/j.redox.2023.102694.
[33]	COOPER DKC. The long and winding road to clinical xenotransplantation: a personal journey[J]. Eur Surg Res, 2022, 63(4): 165-172. DOI: 10.1159/000525757.
[34]	RAMIREZ P, CHAVEZ R, MAJADO M, et al. Transgenic pig-to-baboon liver xenotransplantation: clinical, biochemical, and immunologic pattern of delayed acute vascular rejection[J]. Transplant Proc, 2002, 34(1): 319-320. DOI: 10.1016/s0041-1345(01)02834-2.
[35]	SCHMELZLE M, COWAN PJ, ROBSON SC. Which anti-platelet therapies might be beneficial in xenotransplantation?[J]. Xenotransplantation, 2011, 18(2): 79-87. DOI: 10.1111/j.1399-3089.2011.00628.x.
[36]	MATCZYŃSKA D, SYPNIEWSKI D, GAŁKA S, et al. Analysis of swine leukocyte antigen class I gene profiles and porcine endogenous retrovirus viremia level in a transgenic porcine herd inbred for xenotransplantation research[J]. J Vet Sci, 2018, 19(3): 384-392. DOI: 10.4142/jvs.2018.19.3.384.
[37]	MORTICELLI L, ROSSDAM C, CAJIC S, et al. Genetic knockout of porcine GGTA1 or CMAH/GGTA1 is associated with the emergence of neo-glycans[J]. Xenotransplantation, 2023, 30(4): e12804. DOI: 10.1111/xen.12804.
[38]	CROSS-NAJAFI AA, FARAG K, ISIDAN A, et al. Co-expression of HLA-E and HLA-G on genetically modified porcine endothelial cells attenuates human NK cell-mediated degranulation[J]. Front Immunol, 2023, 14: 1217809. DOI: 10.3389/fimmu.2023.1217809.