异种器官移植过程中预防T细胞排斥反应的研究进展

王雨; 叶学军; 何盛南; 戴一凡; 蔡志明; 牟丽莎

doi:10.3969/j.issn.1674-7445.2017.04.016

异种器官移植过程中预防T细胞排斥反应的研究进展

doi: 10.3969/j.issn.1674-7445.2017.04.016

518037 广东深圳, 深圳市第二人民医院（王雨、何盛南、牟丽莎）; 中山大学（王雨、叶学军、何盛南、蔡志明、牟丽莎）; 南京医科大学（戴一凡）

基金项目:

广东省医学科学技术研究基金项目 A2017129

深圳市三名工程; 深圳市科创委学科布局项目 JCYJ20160229204849975

高水平医学学科建设专项基金 2016031638

深圳市科创委企业工程中心项目 GCZX2015043017281705

深圳市科技计划项目 JCYJ20170306091855136

详细信息

通讯作者:
牟丽莎, Email：molly__molly@163.com

中图分类号: R617, R392.4
计量
- 文章访问数: 245
- HTML全文浏览量: 241
- PDF下载量: 18
- 被引次数: 0
出版历程
- 收稿日期: 2017-05-03
- 网络出版日期: 2021-01-19
- 刊出日期: 2017-07-15

摘要

摘要: 异种器官移植是解决供体器官短缺的最适途径。基因工程已很大程度上克服了异种器官移植出现的超急性排斥反应等早期障碍，但是异种器官的成功存活还需要预防T细胞介导的急性排斥反应。目前异种器官移植中预防T细胞免疫排斥的方案分为3种：从基因水平进行改造减少T细胞免疫排斥反应、直接阻断T细胞免疫排斥反应、诱导移植受体的免疫耐受能力。在临床应用前, 对这些方案进行研究和优化, 有望实现异种器官移植后的长期存活。
- 异种移植 /
- 器官移植 /
- T细胞 /
- 免疫排斥 /
- 基因工程 /
- 猪

HTML全文

表 1 异种器官移植中的T细胞清除和共刺激阻断的文献总结

Table 1. Literature summary of T cell depletion and costimulation blockade in xenotransplantation

T细胞清除	共刺激阻断	移植器官类型	存活时间（d）	文献出处
ATG	-	肾	83	[18, 23]
抗人CD3重组免疫毒素抗体		肾	23	[26]
-	CD28-CD80/86	胰岛	396	[20]
ATG	CD28-CD80/86	心脏	23	[24]
抗CD4抗体(CD4R1) 和抗CD8抗体(M-T807R1)	CD28-CD80/86	肾	21	[27]
ATG	CD40-CD154	心脏	> 500	[28]
ATG	CD40-CD154	肾	136	[29]
抗CD4抗体和抗CD8抗体	CD40-CD154	肾	> 280	[27]

下载: 导出CSV

表 2 异种器官移植免疫耐受诱导的文献总结

Table 2. Literature summary of immune tolerance induction in xenotransplantation

诱导策略	模型	存活时间（d）	文献出处
混合嵌合体	野生型猪至非人灵长类	15	[44]
胸腺联合移植	GTKO型猪至非人灵长类	83	[34]
细胞疗法（MSC）	体外试验	-	[37, 38]
细胞疗法（ECDI）	兔至鼠	> 100	[41]
细胞疗法（Treg）	体外试验	-	[43-44]

下载: 导出CSV

参考文献(44)

[1]	Matas AJ, Smith JM, Skeans MA, et al. OPTN/SRTR 2012 annual data report: kidney[J]. Am J Transplant, 2014, 14(Suppl 1): 11-44. DOI: 10.1111/ajt.12579.
[2]	Cowan PJ, Cooper DK, d' Apice AJ. Kidney xenotransplantation [J]. Kidney Int, 2014, 85(2): 265-275. DOI: 10.1038/ki.2013.381.
[3]	Yang L, Güell M, Niu D, et al. Genome-wide inactivation of porcine endogenous retroviruses (PERVs)[J]. Science, 2015, 350(6264): 1101-1104. DOI: 10.1126/science.aad1191.
[4]	Griesemer A, Yamada K, Sykes M. Xenotransplantation: immunological hurdles and progress toward tolerance [J]. Immunol Rev, 2014, 258(1): 241-258. DOI: 10.1111/imr.12152.
[5]	Scalea J, Hanecamp I, Robson SC, et al. T-cell-mediated immunological barriers to xenotransplantation[J]. Xenotransplantation, 2012, 19(1): 23-30. DOI: 10.1111/j.1399-3089.2011.00687.x.
[6]	Satyananda V, Hara H, Ezzelarab MB, et al. New concepts of immune modulation in xenotransplantation [J]. Transplantation, 2013, 96(11): 937-945. DOI: 10.1097/TP.0b013e31829bbcb2.
[7]	Yamada K, Sachs DH, DerSimonian H. Human anti-porcine xenogeneic T cell response. evidence for allelic specificity of mixed leukocyte reaction and for both direct and indirect pathways of recognition[J]. J Immunol, 1995, 155(11): 5249-5256. http://www.jimmunol.org/content/155/11/5249.short?cited-by=yes;155/11/5249
[8]	Dorling A, Lombardi G, Binns R, et al. Detection of primary direct and indirect human anti-porcine T cell responses using a porcine dendritic cell population[J]. Eur J Immunol, 1996, 26(6): 1378-1387. DOI: 10.1002/eji.1830260630.
[9]	Hering BJ, Walawalkar N. Pig-to-nonhuman primate islet xenotransplantation [J]. Transpl Immunol, 2009, 21(2): 81-86. DOI: 10.1016/j.trim.2009.05.001.
[10]	Phelps CJ, Ball SF, Vaught TD, et al. Production and characterization of transgenic pigs expressing porcine CTLA4-Ig[J]. Xenotransplantation, 2009, 16(6): 477-485. DOI: 10.1111/j.1399-3089.2009.00533.x.
[11]	Koshika T, Phelps C, Fang J, et al. Relative efficiency of porcine and human cytotoxic T-lymphocyte antigen 4 immunoglobulin in inhibiting human CD4+T-cell responses co-stimulated by porcine and human B7 molecules[J]. Immunology, 2011, 134(4): 386-397. DOI: 10.1111/j.1365-2567.2011.03496.x.
[12]	Aron Badin R, Vadori M, Vanhove B. Cell therapy for Parkinson' s disease: a translational approach to assess the role of local and systemic immunosuppression [J]. Am J Transplant, 2016, 16(7): 2016-2029. DOI: 10.1111/ajt.13704.
[13]	Plege-Fleck A, Lieke T, Römermann D, et al. Pig to rat cell transplantation: reduced cellular and antibody responses to xenografts overexpressing PD-L1[J]. Xenotransplantation, 2014, 21(6): 533-542. DOI: 10.1111/xen.12121.
[14]	Ding Q, Lu L, Zhou X, et al. Human PD-L1-overexpressing porcine vascular endothelial cells induce functionally suppressive human CD4+CD25hiFoxp3+Treg cells[J]. J Leukoc Biol, 2011, 90(1): 77-86. DOI: 10.1189/jlb.1210691.
[15]	Plege A, Borns K, Baars W, et al. Suppression of human T-cell activation and expansion of regulatory T cells by pig cells overexpressing PD-ligands[J]. Transplantation, 2009, 87(7): 975-982. DOI: 10.1097/TP.0b013e31819c85e8.
[16]	Hara H, Witt W, Crossley T, et al. Human dominantnegative class Ⅱ transactivator transgenic pigs-effect on the human anti-pig T-cell immune response and immune status[J]. Immunology, 2013, 140(1): 39-46. DOI: 10.1111/imm.12107.
[17]	Cooper DK, Satyananda V, Ekser B, et al. Progress in pig-to-non-human primate transplantation models (1998-2013): a comprehensive review of the literature[J]. Xenotransplantation, 2014, 21(5): 397-419. DOI: 10.1111/xen.12127.
[18]	Servais S, Menten-Dedoyart C, Beguin Y, et al. Impact of pre-transplant anti-T cell globulin (ATG) on immune recovery after myeloablative allogeneic peripheral blood stem cell transplantation[J]. PLoS One, 2015, 10(6): e0130026. DOI: 10.1371/journal.pone.0130026.
[19]	Larsen CP, Pearson TC, Adams AB, et al. Rational development of LEA29Y (belatacept), a high-affinity variant of CTLA4-Ig with potent immunosuppressive properties [J]. Am J Transplant, 2005, 5(3): 443-453. DOI: 10.111/j.1600-6143.2005.00749.x.
[20]	Lenschow DJ, Zeng Y, Thistlethwaite JR, et al. Long-term survival of xenogeneic pancreatic islet grafts induced by CTLA4Ig [J]. Science, 1992, 257(5071): 789-792. doi: 10.1126/science.1323143
[21]	Bühler L, Awwad M, Basker M, et al. High-dose porcine hematopoietic cell transplantation combined with CD40 ligand blockade in baboons prevents an induced anti-pig humoral response [J]. Transplantation, 2000, 69(11): 2296-2304. doi: 10.1097/00007890-200006150-00013
[22]	Barth RN, Yamamoto S, LaMattina JC, et al. Xenogeneic thymokidney and thymic tissue transplantation in a pig-tobaboon model: Ⅰ. evidence for pig-specific T-cell unresponsiveness [J]. Transplantation, 2003, 75(10): 1615-1624. DOI: 10.1097/01.TP.0000064335.50622.20.
[23]	Shimizu A, Yamada K, Robson SC, et al. Pathologic characteristics of transplanted kidney xenografts [J]. J Am Soc Nephrol, 2012, 23(2): 225-235. DOI: 10.1681/ASN.2011040429.
[24]	Iwase H, Ekser B, Satyananda V, et al. Pig-tobaboon heterotopic heart transplantation -exploratory preliminary experience with pigs transgenic for human thrombomodulin and comparison of three costimulation blockade-based regimens [J]. Xenotransplantation, 2015, 22(3): 211-220. DOI: 10.1111/xen.12167.
[25]	Emamaullee JA, Merani S, Larsen CP, et al. Belatacept and basiliximab diminish human antiporcine xenoreactivity and synergize to inhibit alloimmunity [J]. Transplantation, 2008, 85(1): 118-124. DOI: 10.1097/01.tp.0000296832.92128.94.
[26]	Nishimura H, Scalea J, Wang Z, et al. First experience with the use of a recombinant CD3 immunotoxin as induction therapy in pig-to-priate xenotransplantation: the effect of T-cell depletion on outcome [J]. Transplantation, 2011, 92(6): 641-647. DOI: 10.1097/TP.0b013e31822b92a5.
[27]	Higginbotham L, Mathews D, Breeden CA, et al. Pre-transplant antibody screening and anti-CD154 costimulation blockade promote long-term xenograft survival in a pig-to-primate kidney transplant model [J]. Xenotransplantation, 2015, 22(3): 221-230. DOI: 10.1111/xen.12166.
[28]	Mohiuddin MM, Singh AK, Corcoran PC, et al. Genetically engineered pigs and target-specific immunomodulation provide significant graft survival and hope for clinical cardiac xenotransplantation [J]. J Thorac Cardiovasc Surg, 2014, 148(3): 1106-1113. DOI: 10.1016/j.jtcvs.2014.06.002.
[29]	Iwase H, Liu H, Wijkstrom M, et al. Pig kidney graft survival in a baboon for 136 days: longest life-supporting organ graft survival to date [J]. Xenotransplantation, 2015, 22(4): 302-309. DOI: 10.1111/xen.12174.
[30]	Isotani A, Yamagata K, Okabe M, et al. Generation of Hprt-disrupted rat through mouse←rat ES chimeras [J]. Sci Rep, 2016, 6:24215. DOI: 10.1038/srep24215.
[31]	Vogel G. Stem cells. NIH debates human-animal chimeras [J]. Science, 2015, 350(6258): 261-262. DOI: 10.1126/science.350.6258.261.
[32]	Zhao Y, Sergio JJ, Swenson K, et al. Positive and negative selection of functional mouse CD4 cells by porcine MHC in pig thymus grafts [J]. J Immunol, 1997, 159(5): 2100-2107. http://www.jimmunol.org/content/159/5/2100.short?cited-by=yes&legid=jimmunol;159/5/2100
[33]	Khan A, Sergio JJ, Zhao Y, et al. Discordant xenogeneic neonatal thymic transplantation can induce donor-specific tolerance [J]. Transplantation, 1997, 63(1): 124-131. doi: 10.1097/00007890-199701150-00023
[34]	Yamada K, Yazawa K, Shimizu A, et al. Marked prolongation of porcine renal xenograft survival in baboons through the use of alpha1, 3-galactosyltransferase gene-knockout donors and the cotransplantation of vascularized thymic tissue [J]. Nat Med, 2005, 11(1): 32-34. DOI: 10.1038/nm1172.
[35]	Yamada K, Scalea J. Thymic transplantation in pig-to-nonhuman primates for the induction of tolerance across xenogeneic barriers [J]. Methods Mol Biol, 2012, 885: 191-212. DOI: 10.1007/978-1-61779-845-0_12.
[36]	Amarnath S, Foley JE, Farthing DE, et al. Bone marrow-derived mesenchymal stromal cells harness purinergenic signaling to tolerize human Th1 cells in vivo [J]. Stem Cells, 2015, 33(4): 1200-1212. DOI: 10.1002/stem.1934.
[37]	Li J, Ezzelarab MB, Ayares D, et al. The potential role of genetically modified pig mesenchymal stromal cells in xenotransplantation [J]. Stem Cell Rev, 2014, 10(1): 79-85. DOI: 10.1007/s12015-013-9478-8.
[38]	Kumar G, Hara H, Long C, et al. Adipose-derived mesenchymal stromal cells from genetically modified pigs: immunogenicity and immune modulatory properties[J]. Cytotherapy, 2012, 14(4): 494-504. DOI: 10.3109/14653249.2011.651529.
[39]	Li J, Ezzelarab MB, Cooper DK. Do mesenchymal stem cells function across species barriers? relevance for xenotransplantation [J]. Xenotransplantation, 2012, 19(5): 273-285. DOI: 10.1111/xen.12000.
[40]	Chen G, Li J, Chen L, et al. ECDI-fixed allogeneic splenocytes combined with α1-antitrypsin prolong survival of rat renal allografts [J]. Int Immunopharmacol, 2015, 26(1): 43-49. DOI: 10.1016/j.intimp.2015.02.035.
[41]	Wang S, Tasch J, Kheradmand T, et al. Transient B-cell depletion combined with apoptotic donor splenocytes induces xenospecific T-and B-cell tolerance to islet xenografts [J]. Diabetes, 2013, 62(9): 3143-3150. DOI: 10.2337/db12-1678.
[42]	Lin YJ, Hara H, Tai HC, et al. Suppressive efficacy and proliferative capacity of human regulatory T cells in allogeneic and xenogeneic responses [J]. Transplantation, 2008, 86(10): 1452-1462. DOI: 10.1097/TP.0b013e318188acb0.
[43]	Wu J, Yi S, Ouyang L, et al. In vitro expanded human CD4+CD25+ regulatory T cells are potent suppressors of T-cell-mediated xenogeneic responses [J]. Transplantation, 2008, 85(12): 1841-1848. DOI: 10.1097/TP.0b013e3181734793.
[44]	Sablinski T, Gianello P, Bailin M, et al. Pig to monkey bone marrow and kidney xenotransplantation [J]. Surgery, 1997, 121(4): 381-391. doi: 10.1016/S0039-6060(97)90307-X