异种器官移植的进展及展望

doi:10.3969/j.issn.1674-5817.2018.06.001

摘要/Abstract

摘要： 在全球范围内,因终末期器官衰竭而需要器官移植的患者人数不断增加,但从已故或活体捐赠者获得的器官数量非常有限。因此,利用猪器官/组织进行异种移植是解决器官供给短缺的最终办法之一。尽管异种器官移植的研究取得了很大进展,然而,要真正走向临床仍然存在许多障碍,特别是免疫排斥问题。随着该领域研究的不断深入,特别是各种基因编辑技术的发展,实现对猪产生超急性排斥的基因敲除及猪的多种基因进行人源化改造,再在非人类灵长类动物移植模型中进行安全性及功能性评估,移植器官的存活率显著提高。利用CRISPR/Cas9技术将猪内源性逆转录病毒 (PERV)从猪基因组中去除,避免了异种器官移植后内源性病原体感染宿主的潜在风险,具有里程碑意义。本文对异种移植研究需要跨越的障碍、进展、安全、监管和现状等进行了综述。

关键词: 异种移植, 免疫排斥, 猪内源性逆转录病毒(PERV), CRISPR/Cas9

Abstract: Worldwide, the number of patients needing organ transplants for end-stage organ failure is growing, howeverŁ¬ the number of organs available from donation after cardiac death/donation after brain death (DCD/DBD) or living donors is very limited. Therefore, the use of pig organs/tissues for xenotransplantation is one of the final solutions for the shortage of organs. Although tremendous progress has been made in xenotransplantation research, there are still some huge hurdlers, especially immune rejection, in the clinical application of xenotransplantation. With the continuous progress of the field, especially the development of various gene editing technologies, knocking out specific porcine genes which cause hyperacute rejection and humanizing multiple genes in pigs become possible, the survival of transplanted organs in the models of non-human primates has been significantly improved. Moreover, the application of CRISPR/Cas9 technology to remove porcine endogenous retroviruses (PERV) from the pig genome eliminates the potential risk of endogenous pathogens infecting the host after xenotransplantation, which is of landmark significance. This work reviews the barriers, progress, safety, oversight and current status of xenotransplantation.

Key words: Xenotransplantation, Immune rejection, Porcine endogenous retroviruses (PERV), CRISPR/Cas9

中图分类号:

Q95-33

张麒, 王建飞. 异种器官移植的进展及展望[J]. 实验动物与比较医学, 2018, 38(6): 407-411.

ZHANG Qi, WANG Jian-fei. Progress and Perspective for Xenotransplantation[J]. Laboratory Animal and Comparative Medicine, 2018, 38(6): 407-411.

参考文献

[1] Ekser B,Cooper DKC,Tector AJ.The need for xeno-transplantation as a source of organs and cells for clinical transplantation[J].Int J Surg,2015,23(Pt B):199-204.
[2] Mou L,Chen F,Dai Y,et al.Potential alternative approaches to xenotransplantation[J].Int J Surg,2015,23(Pt B):322-326.
[3] Bajic P,Selman SH,Rees MA.Voronoff to virion:1920s testis transplantation and AIDS[J].Xenotransplantation,2012,19(6):337-341.
[4] Cooper DKC,Ekser B,Tector AJ.A brief history of clinical xenotransplantation[J].Int J Surg,2015,23(Pt B):205-210.
[5] Griesemer A,Yamada K,Sykes M.Xenotransplantation:immunological hurdles and progress toward tolerance[J].Immunol Rev,2014,258(1):241-258.
[6] Galili U,Clark MR,Shohet SB,et al.Evolutionary relationship between the natural anti-Gal antibody and the Gal alpha 1-3Gal epitope in primates[J].Proc Natl Acad Sci U S A,1987,84(5):1369-1373.
[7] Cooper DK,Good AH,Koren E,et al.Identification of alpha-galactosyl and other carbohydrate epitopes that are bound by human anti-pig antibodies:relevance to discordant xenografting in man[J].Transpl Immunol,1993,1(3):198-205.
[8] Puga Yung GL,Rieben R,Buhler L,et al.Xenotransplantation:Where do we stand in 2016[J].Swiss Med Wkly,2017,147:w14403.
[9] Wang L,Cooper DKC,Burdorf L,et al.Overcoming coagulation dysregulation in pig solid organ transplantation in nonhuman primates:recent progress[J].Transplantation,2018,102(7):1050-1058.
[10] Noordergraaf J,Schucker A,Martin M,et al.Pathogen elimination and prevention within a regulated,Designated Pathogen Free,closed pig herd for long-term breeding and production of xenotransplantation materials[J].Xenotransplantation,2018,25(4):e12428.
[11] Martin U,Kiessig V,Blusch JH,et al.Expression of pig endogenous retrovirus by primary porcine endothelial cells and infection of human cells[J].Lancet,1998,352(9129):692-694.
[12] Patience C,Takeuchi Y,Weiss RA.Infection of human cells by an endogenous retrovirus of pigs[J].Nat Med,1997,3(3):282-286.
[13] Valdes-Gonzalez R,Dorantes LM,Bracho-Blanchet E,et al.No evidence of porcine endogenous retrovirus in patients with type 1 diabetes after long-term porcine islet xenotransplantation[J].J Med Virol,2010.82(2):331-334.
[14] Paradis K,Langford G,Long Z,et al.Search for cross-species transmission of porcine endogenous retrovirus in patients treated with living pig tissue.The XEN 111 Study Group[J].Science,1999.285(5431):1236-1241.
[15] Niu D,Wei HJ.Inactivation of porcine endogenous retrovirus in pigs using CRISPR-Cas9[J].2017,357(6357):1303-1307.
[16] Yang L,Guell M,Niu D,et al.Genome-wide inactivation of porcine endogenous retroviruses (PERVs)[J].Science,2015,350(6264):1101-1104.
[17] Kim SC,Wakwe W,Higginbotham LB,et al.Fc-silent anti-CD154 domain antibody effectively prevents nonhuman primate renal allograft rejection[J].Am J Transplant,2017,17(5):1182-1192.
[18] 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,2016,7:11138-11138.
[19] Byrne GW,Du Z,Sun Z,et al.Changes in cardiac gene expression after pig-to-primate orthotopic xenotransplantation[J].Xenotransplantation,2011,18(1):14-27.
[20] Cooper DK.Is successful orthotopic heart transplantation in the pig-to-non-human primate model required before proceeding to a clinical trial?[J].Xenotransplantation,2016,23(4):328-329.
[21] 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.
[22] Watanabe H,Sahara H,Nomura S,et al.GalT-KO pig lungs are highly susceptible to acute vascular rejection in baboons,which may be mitigated by transgenic expression of hCD47 on porcine blood vessels[J].2018,25(5):e12391.
[23] Shin JS,Min BH,Kim JM,et al.Failure of transplantation tolerance induction by autologous regulatory T cells in the pig-to-non-human primate islet xenotransplantation model[J].Xenotransplantation,2016,23(4):300-309.
[24] Bloom ET.Xenotransplantation—federal regulatory considerations[J].Curr Top Microbiol Immunol,2003,278:239-251.
[25] Chapman LE.Xenotransplantation,xenogeneic infections,biotechnology,and public health[J].Mt Sinai J Med,2009,76(5):435-441.