肝移植临床免疫抑制剂及新药研究进展

陈泉余; 蒋师放; 夏仁培; 帅领; 张宏宇; 白莲花

doi:10.3969/j.issn.1674-7445.2020.06.003

肝移植临床免疫抑制剂及新药研究进展

doi: 10.3969/j.issn.1674-7445.2020.06.003

400715 重庆,西南大学生命科学学院(陈泉余、白莲花);陆军军医大学西南医院全军肝胆外科研究所(蒋师放、夏仁培、帅领、张宏宇、白莲花)

基金项目:

国家自然科学基金 81571566

国家自然科学基金 81873586

详细信息

作者简介:
陈泉余，男，1994年生，硕士研究生，研究方向为肝移植免疫耐受，Email:13452925856@163.com

通讯作者:
白莲花，女，1963年生，博士，教授，研究方向为肝移植免疫耐受，Email: qqg63@outlook.com

中图分类号: R617;R392.4
计量
- 文章访问数: 458
- HTML全文浏览量: 194
- PDF下载量: 91
- 被引次数: 0
出版历程
- 收稿日期: 2020-08-15
- 网络出版日期: 2021-01-19
- 刊出日期: 2021-01-19

Research progress on immunosuppressants and new drugs for liver transplantation

College of Life Science, Southwest University, Chongqing 400715, China

More Information

Corresponding author: Bai Lianhua, Email: qqg63@outlook.com

摘要

摘要: 肝移植临床常用的免疫抑制剂主要包括钙调磷酸酶抑制剂类药物，如环孢素（CsA）和他克莫司（FK506）等；糖皮质激素类药物，如泼尼松和泼尼松龙等；细胞毒类药物，如硫唑嘌呤、吗替麦考酚酯及环磷酰胺等；哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂类药物，如西罗莫司和依维莫司；抗体类药物如多克隆抗体、单克隆抗体及白细胞介素（IL）-2受体抗体等。免疫抑制剂虽然种类繁多，但目前大多数肝移植受者主要使用FK506。然而，FK506在肝移植后期表现出明显的不良反应，尤其是引起严重感染和肾毒性。因此，研发免疫耐受作用强和不良反应小的新型免疫抑制剂成为临床上迫切需要解决的难题和研究热点。本文就目前肝移植免疫抑制剂的研究进展和新型免疫抑制剂的研发状况进行综述。
- 免疫抑制剂 /
- 排斥反应 /
- 肝移植 /
- 免疫耐受 /
- 不良反应 /
- 淋巴细胞 /
- 信号转导 /
- 单克隆抗体
Abstract: Immunosuppressants, which are commonly used for liver transplantation, mainly included calcineurin inhibitors, such as ciclosporin (CsA) and tacrolimus (FK506); glucocorticoid drugs, such as prednisone and prednisolone; cytotoxic drugs, such as azathioprine, mycophenolate mofetil and cyclophosphamide; mammalian target of rapamycin (mTOR) inhibitors, such as sirolimus and everolimus; antibody drugs, such as polyclonal or monoclonal antibodies and interleukin (IL)-2 receptor antibodies, etc. Although many categories of immunosuppressants are available, FK506 is the most commonly adopted in liver transplant recipients. However, FK506 can provoke significant adverse effects in the late stage of liver transplantation, especially severe infection and nephrotoxicity. Consequently, it is an urgent task and research hot spot to develop new immunosuppressants with strong immune tolerance and mild adverse effects in clinical practice. In this article, the research progress on immunosuppressants and the research and development status of new immunosuppressants for liver transplantation were reviewed.
- Immunosuppressant /
- Rejection /
- Liver transplantation /
- Immune tolerance /
- Adverse effect /
- Lymphocyte /
- Signal transduction /
- Monoclonal antibody

HTML全文

参考文献(69)

[1]	STARZL TE, MARCHIORO TL, VONKAULLA KN, et al. Homotransplantation of the liver in humans[J]. Surg Gynecol Obstet, 1963, 117:659-676. http://europepmc.org/articles/PMC2634660;jsessionid=5u9PFSxWXB2NoZDOvXuO.21
[2]	DUTKOWSKI P, LINECKER M, DEOLIVEIRA ML, et al. Challenges to liver transplantation and strategies to improve outcomes[J]. Gastroenterology, 2015, 148(2):307-323. DOI: 10.1053/j.gastro.2014.08.045.
[3]	ZARRINPAR A, BUSUTTIL RW. Liver transplantation: past, present and future[J]. Nat Rev Gastroenterol Hepatol, 2013, 10(7):434-440. DOI:10.1038/nrgastro. 2013.88.
[4]	NANKIVELL BJ, P'NG CH, O'CONNELL PJ, et al. Calcineurin inhibitor nephrotoxicity through the lens of longitudinal histology: comparison of cyclosporine and tacrolimus eras[J]. Transplantation, 2016, 100(8):1723-1731. DOI: 10.1097/TP.0000000000001243.
[5]	KOROLCZUK A, CABAN K, AMAROWICZ M, et al. Oxidative stress and liver morphology in experimental cyclosporine A-induced hepatotoxicity[J]. Biomed Res Int, 2016:5823271. DOI: 10.1155/2016/5823271.
[6]	TERANO C, ISHIKURA K, HAMADA R, et al. Practical issues in using eculizumab for children with atypical haemolytic uraemic syndrome in the acute phase: a review of four patients[J]. Nephrology (Carlton), 2018, 23(6):539-545. DOI: 10.1111/nep.13054.
[7]	KINO T, HATANAKA H, HASHIMOTO M, et al. FK-506, a novel immunosuppressant isolated from a streptomyces. I. fermentation, isolation, and physico-chemical and biological characteristics[J]. J Antibiot (Tokyo), 1987, 40(9):1249-1255. DOI: 10.7164/antibiotics.40.1249.
[8]	NEUHAUS P, BLUMHARDT G, BECHSTEIN WO, et al. Comparison of FK506- and cyclosporine-based immunosuppression in primary orthotopic liver transplantation. a single center experience[J]. Transplantation, 1995, 59(1):31-40. DOI: 10.1097/00007890-199501150-00007.
[9]	DIEHL R, FERRARA F, MÜLLER C, et al. Immunosuppression for in vivo research: state-of-the-art protocols and experimental approaches[J]. Cell Mol Immunol, 2017, 14(2):146-179. DOI: 10.1038/cmi.2016.39.
[10]	ORANGE DE, BLACHERE NE, FAK J, et al. Dendritic cells loaded with FK506 kill T cells in an antigen-specific manner and prevent autoimmunity in vivo[J]. Elife, 2013, 2:e00105. DOI: 10.7554/eLife.00105.
[11]	WU AH. Creatine kinase isoforms in ischemic heart disease[J]. Clin Chem, 1989, 35(1):7-13. doi: 10.1093/clinchem/35.1.7
[12]	BOREL JF, FEURER C, GUBLER HU, et al. Biological effects of cyclosporin A: a new antilymphocytic agent[J]. Agents Actions, 1976, 6(4):468-475. DOI: 10.1007/BF01973261.
[13]	CALNE RY, ROLLES K, WHITE DJ, et al. Cyclosporin A initially as the only immunosuppressant in 34 recipients of cadaveric organs: 32 kidneys, 2 pancreases, and 2 livers[J]. Lancet, 1979, 2(8151):1033-1036. DOI: 10.1016/s0140-6736(79)92440-1.
[14]	STARZL TE, KLINTMALM GB, PORTER KA, et al. Liver transplantation with use of cyclosporin A and prednisone[J]. N Engl J Med, 1981, 305(5):266-269. DOI: 10.1056/NEJM198107303050507.
[15]	LOESCHENBERGER B, NIESS L, WÜRZNER R, et al. Calcineurin inhibitor-induced complement system activation via ERK1/2 signalling is inhibited by SOCS-3in human renal tubule cells[J]. Eur J Immunol, 2018, 48(2):330-343. DOI: 10.1002/eji.201747135.
[16]	MORTENSEN LA, BISTRUP C, THIESSON HC. Does mineralocorticoid receptor antagonism prevent calcineurin inhibitor-induced nephrotoxicity?[J]. Front Med (Lausanne), 2017, 4:210. DOI: 10.3389/fmed.2017.00210.
[17]	SANDRINI S, SETTI G, BOSSINI N, et al. Early (fifth day) vs. late (sixth month) steroid withdrawal in renal transplant recipients treated with Neoral(®) plus Rapamune(®): four-yr results of a randomized monocenter study[J]. Clin Transplant, 2010, 24(5):669-677. DOI: 10.1111/j.1399-0012.2009.01171.x.
[18]	LIBERMAN AC, BUDZIÑSKI ML, SOKN C, et al. Regulatory and mechanistic actions of glucocorticoids on T and inflammatory cells[J]. Front Endocrinol (Lausanne), 2018, 9:235. DOI: 10.3389/fendo.2018.00235.
[19]	EHRCHEN JM, ROTH J, BARCZYK-KAHLERT K. More than suppression: glucocorticoid action on monocytes and macrophages[J]. Front Immunol, 2019, 10:2028. DOI: 10.3389/fimmu.2019.02028.
[20]	COOPER DKC. Early clinical xenotransplantation experiences-an interview with Thomas E. Starzl, MD, PhD[J]. Xenotransplantation, 2017, 24(2). DOI: 10.1111/xen.12306.
[21]	FUNG JJ. Obituary of Thomas E. Starzl, MD, PhD[J]. Am J Transplant, 2017, 17(5):1153-1155. DOI: 10.1111/ajt.14267.
[22]	HEIDEVELD E, HAMPTON-O'NEIL LA, CROSS SJ, et al. Glucocorticoids induce differentiation of monocytes towards macrophages that share functional and phenotypical aspects with erythroblastic island macrophages[J]. Haematologica, 2018, 103(3):395-405. DOI: 10.3324/haematol.2017.179341.
[23]	VANDEWALLE J, LUYPAERT A, DE BOSSCHER K, et al. Therapeutic mechanisms of glucocorticoids[J]. Trends Endocrinol Metab, 2018, 29(1):42-54. DOI: 10.1016/j.tem.2017.10.010.
[24]	RONCHETTI S, MIGLIORATI G, BRUSCOLI S, et al. Defining the role of glucocorticoids in inflammation[J]. Clin Sci (Lond), 2018, 132(14):1529-1543. DOI: 10.1042/CS20171505.
[25]	MA WT, GAO F, GU K, et al. The role of monocytes and macrophages in autoimmune diseases: a comprehensive review[J]. Front Immunol, 2019, 10:1140. DOI: 10.3389/fimmu.2019.01140.
[26]	KUMAR D, SEHRAWAT S. Divergent effects of a transient corticosteroid therapy on virus-specific quiescent and effector CD8⁺ T cells[J]. Front Immunol, 2019, 10:1521. DOI: 10.3389/fimmu.2019.01521.
[27]	COUTINHO AE, CHAPMAN KE. The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights[J]. Mol Cell Endocrinol, 2011, 335(1):2-13. DOI: 10.1016/j.mce.2010.04.005.
[28]	FERRARA G, PETRILLO MG, GIANI T, et al. Clinical use and molecular action of corticosteroids in the pediatric age[J]. Int J Mol Sci, 2019, 20(2):444. DOI: 10.3390/ijms20020444.
[29]	ZHANG J, YANG Y, LIU W, et al. Glucocorticoid and mineralocorticoid receptors and corticosteroid homeostasis are potential targets for endocrine-disrupting chemicals[J]. Environ Int, 2019, 133(Pt A):105133. DOI: 10.1016/j.envint.2019.105133.
[30]	RADHAKUTTY A, BURT MG. Management of endocrine disease: critical review of the evidence underlying management of glucocorticoid-induced hyperglycaemia[J]. Eur J Endocrinol, 2018, 179(4):R207-R218. DOI: 10.1530/EJE-18-0315.
[31]	HERNÁNDEZ-DÍAZ S, RODRÍGUEZ LA. Steroids and risk of upper gastrointestinal complications[J]. Am J Epidemiol, 2001, 153(11):1089-1093. DOI: 10.1093/aje/153.11.1089.
[32]	WHITTIER X, SAAG KG. Glucocorticoid-induced osteoporosis[J]. Rheum Dis Clin North Am, 2016, 42(1):177-x. DOI: 10.1016/j.rdc.2015.08.005.
[33]	GUPTA S, SHAH P, GREWAL S, et al. Steroid-induced glaucoma and childhood blindness[J]. Br J Ophthalmol, 2015, 99(11):1454-1456. DOI: 10.1136/bjophthalmol-2014-306557.
[34]	CARA CJ, PENA AS, SANS M, et al. Reviewing the mechanism of action of thiopurine drugs: towards a new paradigm in clinical practice[J]. Med Sci Monit, 2004, 10(11):RA247-RA254. http://www.ncbi.nlm.nih.gov/pubmed/15507865
[35]	GŁADYSZ M, ANDRAŁOJĆ W, CZAPIK T, et al. Thermodynamic and structural contributions of the 6-thioguanosine residue to helical properties of RNA[J]. Sci Rep, 2019, 9(1):4385. DOI: 10.1038/s41598-019-40715-2.
[36]	LEITNER J, DROBITS K, PICKL WF, et al. The effects of cyclosporine A and azathioprine on human T cells activated by different costimulatory signals[J]. Immunol Lett, 2011, 140(1/2):74-80. DOI:10.1016/j.imlet. 2011.06.010.
[37]	COULTHARD SA, BERRY P, MCGARRITY S, et al. Azathioprine with allopurinol: lower deoxythioguanosine in DNA and transcriptome changes indicate mechanistic differences to azathioprine alone[J]. Inflamm Bowel Dis, 2017, 23(6):946-955. DOI:10.1097/MIB. 0000000000001131.
[38]	TSUCHIYA A, AOMORI T, SAKAMOTO M, et al. Effect of genetic polymorphisms of azathioprine-metabolizing enzymes on response to rheumatoid arthritis treatment[J]. Pharmazie, 2017, 72(1):22-28. DOI: 10.1691/ph.2017.6799.
[39]	CUMMINS D, SEKAR M, HALIL O, et al. Myelosuppression associated with azathioprine-allopurinol interaction after heart and lung transplantation[J]. Transplantation, 1996, 61(11):1661-1662. DOI: 10.1097/00007890-199606150-00023.
[40]	PEYRIN-BIROULET L, CADRANEL JF, NOUSBAUM JB, et al. Interaction of ribavirin with azathioprine metabolism potentially induces myelosuppression[J]. Aliment Pharmacol Ther, 2008, 28(8):984-993. DOI: 10.1111/j.1365-2036.2008.03812.x.
[41]	SIEBERT A, PREJS M, CHOLEWINSKI G, et al. New analogues of mycophenolic acid[J]. Mini Rev Med Chem, 2017, 17(9):734-745. DOI: 10.2174/1389557516666161129160001.
[42]	HOSOHATA K, MATSUOKA E, INADA A, et al. Differential profiles of adverse events associated with mycophenolate mofetil between adult and pediatric renal transplant patients[J]. J Int Med Res, 2018, 46(11):4617-4623. DOI: 10.1177/0300060518786917.
[43]	WANG WX, CHENG GG, LI ZH, et al. Curtachalasins, immunosuppressive agents from the endophytic fungus xylaria cf. curta[J]. Org Biomol Chem, 2019, 17(34):7985-7994. DOI: 10.1039/c9ob01552c.
[44]	GO E, TARNAWSKY SP, SHELLEY WC, et al. Mycophenolic acid induces senescence of vascular precursor cells[J]. PLoS One, 2018, 13(3):e0193749. DOI: 10.1371/journal.pone.0193749.
[45]	ISHIKAWA Y, KASUYA T, ISHIKAWA J, et al. A case of developing progressive multifocal leukoencephalopathy while using rituximab and mycophenolate mofetil in refractory systemic lupus erythematosus[J]. Ther Clin Risk Manag, 2018, 14:1149-1153. DOI: 10.2147/TCRM.S167109.
[46]	MARTÍN MC, CRISTIANO E, VILLANUEVA M, et al. Esophageal atresia and prenatal exposure to mycophenolate[J]. Reprod Toxicol, 2014, 50:117-121. DOI: 10.1016/j.reprotox.2014.10.015.
[47]	HUANG CP, CHEN CC, TSAI YT, et al. Intravesical administration of xenogeneic porcine urothelial cells attenuates cyclophosphamide-induced cystitis in mice[J]. Cell Transplant, 2019, 28(3):296-305. DOI: 10.1177/0963689718822773.
[48]	ŠTENGLOVÁ NETÍKOVÁ IR, PETRUŽELKA L, ŠŤASTNÝ M, et al. Safe decontamination of cytostatics from the nitrogen mustards family. part one: cyclophosphamide and ifosfamide[J] Int J Nanomedicine, 2018, 13:7971-7985. DOI: 10.2147/IJN.S159328.
[49]	CLARK KL, KEATING AF. Ataxia-telangiectasia mutated coordinates the ovarian DNA repair and atresia-initiating response to phosphoramide mustard[J]. Biol Reprod, 2020, 102(1):248-260. DOI: 10.1093/biolre/ioz160.
[50]	TECZA K, PAMULA-PILAT J, LANUSZEWSKA J, et al. Pharmacogenetics of toxicity of 5-fluorouracil, doxorubicin and cyclophosphamide chemotherapy in breast cancer patients[J]. Oncotarget, 2018, 9(10):9114-9136. DOI: 10.18632/oncotarget.24148.
[51]	SUN X, ZHAO YN, QIAN S, et al. Ginseng-derived panaxadiol saponins promote hematopoiesis recovery in cyclophosphamide-induced myelosuppressive mice: potential novel treatment of chemotherapy-induced cytopenias[J]. Chin J Integr Med, 2018, 24(3):200-206. DOI: 10.1007/s11655-017-2754-8.
[52]	MIELCAREK M, FURLONG T, O'DONNELL PV, et al. Posttransplantation cyclophosphamide for prevention of graft-versus-host disease after HLA-matched mobilized blood cell transplantation[J]. Blood, 2016, 127(11):1502-1508. DOI: 10.1182/blood-2015-10-672071.
[53]	FLOYD JD, NGUYEN DT, LOBINS RL, et al. Cardiotoxicity of cancer therapy[J]. J Clin Oncol, 2005, 23(30):7685-7696. DOI: 10.1200/JCO.2005.08.789.
[54]	MARTEL RR, KLICIUS J, GALET S. Inhibition of the immune response by rapamycin, a new antifungal antibiotic[J]. Can J Physiol Pharmacol, 1977, 55(1):48-51. DOI: 10.1139/y77-007.
[55]	KLAWITTER J, NASHAN B, CHRISTIANS U. Everolimus and sirolimus in transplantation-related but different[J]. Expert Opin Drug Saf, 2015, 14(7):1055-1070. DOI: 10.1517/14740338.2015.1040388.
[56]	WONG M. Mammalian target of rapamycin (mTOR) pathways in neurological diseases[J]. Biomed J, 2013, 36(2):40-50. DOI: 10.4103/2319-4170.110365.
[57]	HOEGH-PETERSEN M, AMIN MA, LIU Y, et al. Anti-thymocyte globulins capable of binding to T and B cells reduce graft-vs-host disease without increasing relapse[J]. Bone Marrow Transplant, 2013, 48(1):105-114. DOI: 10.1038/bmt.2012.99.
[58]	COSIMI AB, COLVIN RB, BURTON RC, et al. Use of monoclonal antibodies to T-cell subsets for immunologic monitoring and treatment in recipients of renal allografts[J]. N Engl J Med, 1981, 305(6):308-314. DOI: 10.1056/NEJM198108063050603.
[59]	OTTO G, THIES J, KRAUS T, et al. Monoclonal anti-CD25 for acute rejection after liver transplantation[J]. Lancet, 1991, 338(8760):195. DOI: 10.1016/0140-6736(91)90192-r.
[60]	WARD NC, YU A, MORO A, et al. IL-2/CD25: a long-acting fusion protein that promotes immune tolerance by selectively targeting the IL-2 receptor on regulatory T cells[J]. J Immunol, 2018, 201(9):2579-2592. DOI: 10.4049/jimmunol.1800907.
[61]	BAAN CC, KANNEGIETER NM, FELIPE CR, et al. Targeting JAK/STAT signaling to prevent rejection after kidney transplantation: a reappraisal[J]. Transplantation, 2016, 100(9):1833-1839. DOI: 10.1097/TP.0000000000001226.
[62]	PÉREZ-JELDRES T, TYLER CJ, BOYER JD, et al. Targeting cytokine signaling and lymphocyte traffic via small molecules in inflammatory bowel disease: JAK inhibitors and S1PR agonists[J]. Front Pharmacol, 2019, 10:212. DOI: 10.3389/fphar.2019.00212.
[63]	ANIL KUMAR MS, PAPP K, TAINAKA R, et al. Randomized, controlled study of bleselumab (ASKP1240) pharmacokinetics and safety in patients with moderate-to-severe plaque psoriasis[J]. Biopharm Drug Dispos, 2018, 39(5):245-255. DOI: 10.1002/bdd.2130.
[64]	GOLDWATER R, KEIRNS J, BLAHUNKA P, et al. A phase 1, randomized ascending single-dose study of antagonist anti-human CD40 ASKP1240 in healthy subjects[J]. Am J Transplant, 2013, 13(4):1040-1046. DOI: 10.1111/ajt.12082.
[65]	VINCENTI F, KLINTMALM G, YANG H, et al. A randomized, phase 1b study of the pharmacokinetics, pharmacodynamics, safety, and tolerability of bleselumab, a fully human, anti-CD40 monoclonal antibody, in kidney transplantation[J]. Am J Transplant, 2020, 20(1):172-180. DOI: 10.1111/ajt.15560.
[66]	O'CONNELL PJ, KUYPERS DR, MANNON RB, et al. Clinical trials for immunosuppression in transplantation: the case for reform and change in direction[J]. Transplantation, 2017, 101(7):1527-1534. DOI: 10.1097/TP.0000000000001648.
[67]	LIU Q, SMITH AR, PARK JM, et al. The adoption of generic immunosuppressant medications in kidney, liver, and heart transplantation among recipients in Colorado or nationally with medicare part D[J]. Am J Transplant, 2018, 18(7):1764-1773. DOI: 10.1111/ajt.14722.
[68]	ROUSSEAU B, GUILLEMIN A, DUVOUX C, et al. Optimal oncologic management and mTOR inhibitor introduction are safe and improve survival in kidney and liver allograft recipients with de novo carcinoma[J]. Int J Cancer, 2019, 144(4):886-896. DOI: 10.1002/ijc.31769.
[69]	BENKHOUCHA M, MOLNARFI N, KAYA G, et al. Identification of a novel population of highly cytotoxic c-Met-expressing CD8⁺ T lymphocytes[J].EMBO Rep, 2017, 18(9):1545-1558. DOI:10.15252/embr. 201744075.