国内外异种器官移植的现状及进展

张小燕; 王国辉; 韩士超; 戚若晨; 刘克普; 魏迪; 杨晓剑; 马帅军; 窦科峰; 秦卫军

doi:10.3969/j.issn.1674-7445.2023193

国内外异种器官移植的现状及进展

doi: 10.3969/j.issn.1674-7445.2023193

710032　西安，空军军医大学西京医院泌尿外科

基金项目: 国家自然科学基金（82101322、82200845）

详细信息

作者简介:

通讯作者:
窦科峰（ORCID 0000-0003-1708-8048），主任医师，中国科学院院士，研究方向为异种移植与肝胆疾病，Email: doukef@fmmu.edu.cn；秦卫军（ORCID 0000-0001-5202-642X），博士，主任医师，研究方向为肾移植与泌尿系肿瘤，Email: doukef@fmmu.edu.cn

中图分类号: R617,Q78
计量
- 文章访问数: 265
- HTML全文浏览量: 166
- PDF下载量: 68
- 被引次数: 0
出版历程
- 收稿日期: 2023-12-05
- 网络出版日期: 2024-01-24
- 刊出日期: 2024-03-15

Present situation and progress of xenotransplantation at home and abroad

Department of Urology, Xijing Hospital of Air Force Medical University, Xi’an 710032, China

More Information

Corresponding author: Dou Kefeng, Email: doukef@fmmu.edu.cn; Qin Weijun, Email: qinwj@fmmu.edu.cn

摘要

摘要: 器官短缺已成为阻碍器官移植发展的主要难题，异种移植是解决全球器官匮乏最有价值的方法之一。近年来，基因工程技术的发展和新型免疫抑制药的研发为异种移植提供了新的理论基础。国外陆续开展基因修饰猪-非人灵长类动物或脑死亡受者的相关异种移植研究，并取得一些实质性的进展，但大部分的研究仍处于临床前阶段，距离投入临床跨越巨大。因此，本文结合目前国内外最新的临床前实验研究进展，对异种移植的历史、基因修饰技术发展、异种移植排斥反应及免疫抑制方案等问题进行综述，以期为异种移植的进一步研究提供参考，促进异种移植临床应用，造福更多终末期疾病患者。
- 异种移植 /
- 基因修饰猪 /
- 免疫抑制药 /
- 非人灵长类动物 /
- 排斥反应 /
- 炎症反应 /
- 凝血功能障碍 /
- 感染
Abstract: Organ shortage has become one of the major challenges hindering the development of organ transplantation. Xenotransplantation is one of the most valuable methods to resolve global organ shortage. In recent years, the development of genetic engineering technique and research and development of new immunosuppressant have provided novel theoretical basis for xenotransplantation. International scholars have successively carried out researches on xenotransplantation in genetically modified pigs to non-human primates or brain death recipients, making certain substantial progresses. However, most of the researches are still in the preclinical stage, far from clinical application. Therefore, according to the latest preclinical experimental research progress at home and abroad, the history of xenotransplantation, the development of gene modification technology, xenotransplantation rejection and immunosuppression regimens were reviewed, aiming to provide reference for subsequent research of xenotransplantation, promote clinical application of xenotransplantation and bring benefits to more patients with end-stage diseases.
- Xenotransplantation /
- Genetically modified pig /
- Immunosuppressant /
- Non-human primate /
- Rejection /
- Inflammation /
- Coagulation disorder /
- Infection

HTML全文

FIG. 3000. FIG. 3000.

FIG. 3000.. FIG. 3000.

下载: 全尺寸图片幻灯片

图 1 基因修饰猪-人移植排斥反应、凝血及炎症反应

注：PAF-1为血小板激活因子1；HLA-E为人类白细胞抗原E抗体。

Figure 1. Rejection, coagulation and inflammation in genetically modified pig to human transplantation

下载: 全尺寸图片幻灯片

参考文献(43)

[1]	WANG X, MO Y, YUAN Y, et al. Exploring the influencing factors of unmet palliative care needs in Chinese patients with end-stage renal disease undergoing maintenance hemodialysis: a cross-sectional study[J]. BMC Palliat Care, 2023, 22(1): 113. DOI: 10.1186/s12904-023-01237-x.
[2]	LENTINE KL, SMITH JM, HART A, et al. OPTN/SRTR 2020 annual data report: kidney[J]. Am J Transplant, 2022, 22(Suppl 2): 21-136. DOI: 10.1111/ajt.16982.
[3]	HUANG J. Expert consensus on clinical trials of human xenotransplantation in China[J]. Health Care Sci, 2022, 1: 7-10. DOI: 10.1002/hcs2.6.
[4]	PEREIRA-MARTINS DA, WEINHÄUSER I, COELHO-SILVA JL, et al. MLL5 improves ATRA driven differentiation and promotes xenotransplant engraftment in acute promyelocytic leukemia model[J]. Cell Death Dis, 2021, 12(4): 371. DOI: 10.1038/s41419-021-03604-z.
[5]	COOPER DKC, GASTON R, ECKHOFF D, et al. Xenotransplantation-the current status and prospects[J]. Br Med Bull, 2018, 125(1): 5-14. DOI: 10.1093/bmb/ldx043.
[6]	LAI L, KOLBER-SIMONDS D, PARK KW, et al. Production of alpha-1, 3-galactosyltransferase knockout pigs by nuclear transfer cloning[J]. Science, 2002, 295(5557): 1089-1092. DOI: 10.1126/science.1068228.
[7]	SYKES M, SACHS DH. Progress in xenotransplantation: overcoming immune barriers[J]. Nat Rev Nephrol, 2022, 18(12): 745-761. DOI: 10.1038/s41581-022-00624-6.
[8]	MOAZAMI N, STERN JM, KHALIL K, et al. Pig-to-human heart xenotransplantation in two recently deceased human recipients[J]. Nat Med, 2023, 29(8): 1989-1997. DOI: 10.1038/s41591-023-02471-9.
[9]	ZHANG X, WANG Q, ZHAO J, et al. The resurgent landscape of xenotransplantation of pig organs in nonhuman primates[J]. Sci China Life Sci, 2021, 64(5): 697-708. DOI: 10.1007/s11427-019-1806-2.
[10]	ARABI TZ, SABBAH BN, LERMAN A, et al. Xenotransplantation: current challenges and emerging solutions[J]. Cell Transplant, 2023, 32: 9636897221148771. DOI: 10.1177/09636897221148771.
[11]	LÄNGIN M, MAYR T, REICHART B, et al. Consistent success in life-supporting porcine cardiac xenotransplantation[J]. Nature, 2018, 564(7736): 430-433. DOI: 10.1038/s41586-018-0765-z.
[12]	KIM SC, MATHEWS DV, BREEDEN CP, et al. Long-term survival of pig-to-rhesus macaque renal xenografts is dependent on CD4 T cell depletion[J]. Am J Transplant, 2019, 19(8): 2174-2185. DOI: 10.1111/ajt.15329.
[13]	GRIFFITH BP, GOERLICH CE, SINGH AK, et al. Genetically modified porcine-to-human cardiac xenotransplantation[J]. N Engl J Med, 2022, 387(1): 35-44. DOI: 10.1056/NEJMoa2201422.
[14]	LOCKE JE, KUMAR V, ANDERSON D, et al. Normal graft function after pig-to-human kidney xenotransplant[J]. JAMA Surg, 2023, 158(10): 1106-1108. DOI: 10.1001/jamasurg.2023.2774.
[15]	LI J, XU Y, ZHANG J, et al. Single-cell transcriptomic analysis reveals transcriptional and cell subpopulation differences between human and pig immune cells[J]. Genes Genomics, 2024, 46(3): 303-322. DOI: 10.1007/s13258-023-01456-9.
[16]	MATSUMOTO S, ABALOVICH A, WYNYARD S, et al. Patients' opinions 10 years after receiving encapsulated porcine islet xenotransplantation without immunosuppression[J]. Xenotransplantation, 2023, 30(3): e12798. DOI: 10.1111/xen.12798.
[17]	王维, 莫朝辉, 叶斌, 等. 新生猪胰岛移植治疗糖尿病病人的临床研究[J]. 中南大学学报(医学版), 2011, 36(12): 1134-1140. DOI: 10.3969/j.issn.1672-7347.2011.12.002. WANG W, MO ZH, YE B, et al. A clinical trial of xenotransplantation of neonatal pig islets for diabetic patients[J]. J Cent South Univ (Med Sci), 2011, 36(12): 1134-1140. DOI: 10.3969/j.issn.1672-7347.2011.12.002.
[18]	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 X, WANG L, ZHANG HT, et al. Preliminary report of preclinical trial of multi-genome engineering pig-to-macaque heart, liver and kidney transplantation[J]. Organ Transplant, 2021, 12(1): 51-56. DOI: 10.3969/j.issn.1674-7445.2021.01.008.
[19]	FENG H, LI T, DU J, et al. Both natural and induced anti-sda antibodies play important roles in GTKO pig-to-rhesus monkey xenotransplantation[J]. Front Immunol, 2022, 13: 849711. DOI: 10.3389/fimmu.2022.849711.
[20]	杨树军, 卫浩, 许勇, 等. 六基因编辑猪-食蟹猴异种肾移植围手术期监测初步报道[J]. 器官移植, 2023, 14(4): 521-528. DOI: 10.3969/j.issn.1674-7445.2023.04.008. YANG SJ, WEI H, XU Y, et al. Preliminary report of perioperative monitoring of six-gene-edited pig-to-cynomolgus monkey kidney xenotransplantation[J]. Organ Transplant, 2023, 14(4): 521-528. DOI: 10.3969/j.issn.1674-7445.2023.04.008.
[21]	高菲, 王煜, 杜嘉祥, 等. 遗传修饰猪模型在生物医学及农业领域研究进展及应用[J]. 遗传, 2023, 45(1): 6-28. DOI: 10.16288/j.yczz.22-313. GAO F, WANG Y, DU JX, et al. Advances and applications of genetically modified pig models in biomedical and agricultural field[J]. Hereditas, 2023, 45(1): 6-28. DOI: 10.16288/j.yczz.22-313.
[22]	淮国丽, 杜嘉祥, 潘登科. 基因编辑猪用于急性肝衰竭治疗的路径探讨[J]. 临床肝胆病杂志, 2022, 38(10): 2214-2218. DOI: 10.3969/j.issn.1001-5256.2022.10.004. HUAI GL, DU JX, PAN DK. The discussion on the genetically modified pigs for the treatment of acute liver failure[J]. J Clin Hepatol, 2022, 38(10): 2214-2218. DOI: 10.3969/j.issn.1001-5256.2022.10.004.
[23]	HARISA GI, FARIS TM, SHERIF AY, et al. Gene-editing technology, from macromolecule therapeutics to organ transplantation: applications, limitations, and prospective uses[J]. Int J Biol Macromol, 2023, 253(Pt 5): 127055. DOI: 10.1016/j.ijbiomac.2023.127055.
[24]	GANCHIKU Y, RIELLA LV. Pig-to-human kidney transplantation using brain-dead donors as recipients: one giant leap, or only one small step for transplantkind?[J]. Xenotransplantation, 2022, 29(3): e12748. DOI: 10.1111/xen.12748.
[25]	DENNER J. Microchimerism, PERV and xenotransplantation[J]. Viruses, 2023, 15(1): 190. DOI: 10.3390/v15010190.
[26]	NIU D, WEI HJ, LIN L, et al. Inactivation of porcine endogenous retrovirus in pigs using CRISPR-Cas9[J]. Science, 2017, 357(6357): 1303-1307. DOI: 10.1126/science.aan4187.
[27]	窦科峰, 张玄. 临床异种器官移植十大问题的思考[J]. 器官移植, 2022, 13(4): 411-416. DOI: 10.3969/j.issn.1674-7445.2022.04.001. DOU KF, ZHANG X. Reflection on 10 problems of clinical xenotransplantation[J]. Organ Transplant, 2022, 13(4): 411-416. DOI: 10.3969/j.issn.1674-7445.2022.04.001.
[28]	MOHIUDDIN MM, SINGH AK, CORCORAN PC, et al. Chimeric 2C10R4 anti-CD40 antibody therapy is critical for long-term survival of GTKO. hCD46. hTBM pig-to-primate cardiac xenograft[J]. Nat Commun, 2016, 7: 11138. DOI: 10.1038/ncomms11138.
[29]	BIKHET M, IWASE H, YAMAMOTO T, et al. What therapeutic regimen will be optimal for initial clinical trials of pig organ transplantation?[J]. Transplantation, 2021, 105(6): 1143-1155. DOI: 10.1097/TP.0000000000003622.
[30]	SÖLLNER JH, METTENLEITER TC, PETERSEN B. Genome editing strategies to protect livestock from viral infections[J]. Viruses, 2021, 13(10): 1996. DOI: 10.3390/v13101996.
[31]	LOVELAND BE, MILLAND J, KYRIAKOU P, et al. Characterization of a CD46 transgenic pig and protection of transgenic kidneys against hyperacute rejection in non-immunosuppressed baboons[J]. Xenotransplantation, 2004, 11(2): 171-183. DOI: 10.1046/j.1399-3089.2003.00103.x.
[32]	CHABAN R, COOPER DKC, PIERSON RN 3RD. Pig heart and lung xenotransplantation: present status[J]. J Heart Lung Transplant, 2022, 41(8): 1014-1022. DOI: 10.1016/j.healun.2022.04.010.
[33]	DELAURA I, ANWAR IJ, LADOWSKI J, et al. Attitudes of patients with renal disease on xenotransplantation: a systematic review[J]. Xenotransplantation, 2023, 30(2): e12794. DOI: 10.1111/xen.12794.
[34]	COOPER DKC, HARA H, IWASE H, et al. Justification of specific genetic modifications in pigs for clinical organ xenotransplantation[J]. Xenotransplantation, 2019, 26(4): e12516. DOI: 10.1111/xen.12516.
[35]	DENNER J. The origin of porcine endogenous retroviruses (PERVs)[J]. Arch Virol, 2021, 166(4): 1007-1013. DOI: 10.1007/s00705-020-04925-8.
[36]	WAHID B, USMAN S, ALI A, et al. Therapeutic strategies of clustered regularly interspaced palindromic repeats-cas systems for different viral infections[J]. Viral Immunol, 2017, 30(8): 552-559. DOI: 10.1089/vim.2017.0055.
[37]	LIU Y, QIN L, TONG R, et al. Regulatory changes in China on xenotransplantation and related products[J]. Xenotransplantation, 2020, 27(3): e12601. DOI: 10.1111/xen.12601.
[38]	COOPER DKC, HARA H, IWASE H, et al. Clinical pig kidney xenotransplantation: how close are we?[J]. J Am Soc Nephrol, 2020, 31(1): 12-21. DOI: 10.1681/ASN.2019070651.
[39]	FISHMAN JA. Prevention of infection in xenotransplantation: designated pathogen-free swine in the safety equation[J]. Xenotransplantation, 2020, 27(3): e12595. DOI: 10.1111/xen.12595.
[40]	YAMAMOTO T, IWASE H, PATEL D, et al. Old world monkeys are less than ideal transplantation models for testing pig organs lacking three carbohydrate antigens (triple-knockout)[J]. Sci Rep, 2020, 10(1): 9771. DOI: 10.1038/s41598-020-66311-3.
[41]	MOHIUDDIN MM, SINGH AK, SCOBIE L, et al. Graft dysfunction in compassionate use of genetically engineered pig-to-human cardiac xenotransplantation: a case report[J]. Lancet, 2023, 402(10399): 397-410. DOI: 10.1016/S0140-6736(23)00775-4.
[42]	PULLEN LC. Xenotransplant: coming soon?[J]. Am J Transplant, 2022, 22(4): 1003-1004. DOI: 10.1111/ajt.16651.
[43]	TECTOR AJ, ADAMS AB, TECTOR M. Current status of renal xenotransplantation and next steps[J]. Kidney360, 2023, 4(2): 278-284. DOI: 10.34067/KID.0007152021.