您的位置：山东大学 -> 科技期刊社 -> 《山东大学学报（医学版）》

山东大学学报（医学版） ›› 2016, Vol. 54 ›› Issue (4): 11-16.doi: 10.6040/j.issn.1671-7554.0.2015.796

• • 上一篇    下一篇

AG490对实验性自身免疫性重症肌无力大鼠的治疗作用

陈慧1,李亨1,岳龙涛2,张民1,王聪聪1,王杉1,张蓬1,段瑞生1   

  1. 山东大学附属千佛山医院 1.神经内科;2.中心实验室, 山东 济南 250014
  • 收稿日期:2015-08-21 出版日期:2016-04-10 发布日期:2016-04-10
  • 通讯作者: 段瑞生. E-mail: ruisheng_duan@yahoo.com E-mail:ruisheng_duan@yahoo.com
  • 基金资助:
    山东省泰山学者建设工程专项经费(20130914);国家自然科学基金(81471222)

Therapeutic effects of AG490 on experimental autoimmune myasthenia gravis in Lewis rats

CHEN Hui1, LI Heng1, YUE Longtao2, ZHANG Min1, WANG Congcong1, WANG Shan1, ZHANG Peng1, DUAN Ruisheng1   

  1. 1. Department of Neurology;
    2.Central Laboratory, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, Shandong, China
  • Received:2015-08-21 Online:2016-04-10 Published:2016-04-10

PDF (PC)

506

摘要： 目的 探讨JAK2/STAT3通路抑制剂AG490对实验性自身免疫性重症肌无力(EAMG)大鼠的治疗作用。 方法 用人工合成的大鼠乙酰胆碱受体α亚基的97-116肽段免疫Lewis大鼠,建立EAMG模型,将12只大鼠随机、平均分为AG490治疗组及对照组,双盲法隔日评估大鼠临床症状并评分。流式细胞术检测淋巴结单个核细胞中细胞因子IL-6及IL-21的分泌;CCK-8及羟基荧光素琥珀酰亚胺酯(CFSE)检测淋巴结单个核细胞的增殖;ELISA检测大鼠血清中抗R97-116抗体水平。 结果 自免疫后第13天开始,AG490治疗组临床症状较对照组明显缓解,并且第27、29、31、33、37、39、41天时,两组肌力评分的差异有统计学意义(P<0.05);与对照组相比,AG490治疗组中的细胞因子IL-6、IL-21的分泌减少(P<0.01);AG490治疗组中抗R97-116抗体IgG、IgG2b的分泌减少(P<0.01);与对照组相比,AG490治疗组的淋巴细胞的增殖受到抑制。 结论 AG490通过抑制细胞因子IL-6及IL-21的分泌,降低大鼠血清中抗R97-116抗体IgG、IgG2b水平,缓解EAMG大鼠病情。

关键词: 实验性自身免疫性重症肌无力, AG490, IL-6, IL-21, 抗R97-116抗体

Abstract: Objective To investigate the effect of AG490 on Lewis rats with experimental autoimmune myasthenia gravis(EAMG). Methods The EAMG model was established by immunization of Lewis rats with R97-116 peptide. Twelve rats were randomly divided into two groups(n=6 in each group), i.e, the control group and the AG490 treatment group. The levels of intracellular IL-6 and IL-21 were analyzed by flow cytometry. The lymphocyte proliferation was determined by CCK-8 and CFSE. Anti-R97-116 IgG and subtypes in the serum were detected by ELISA. Results From day 13 after immunization, the clinical symptoms of the AG490 group were obviously ameliorated, especially on day 27, 29, 31, 33, 37, 39 and 41(P<0.05), compared with the control group. Besides this, the AG490 treatment group also showed decreased secretion of IL-6 and IL-21(P<0.01), reduced anti-R97-116 peptide IgG and IgG2b(P<0.01), and suppressed lymphocyte(in particular CD4+ T cells)proliferation, compared with the control group. Conclusion AG490 can ameliorate EAMG by down-regulating the secretion of IL-6 and IL-21, which further reduces anti-R97-116 peptide IgG and IgG2b.

Key words: Anti-R97-116 antibody, AG490, IL-21, Experimental autoimmune myasthenia gravis, IL-6

中图分类号: 

  • R746.1
[1] Ha JC, Richman DP. Myasthenia gravis and related disorders:pathology and molecular pathogenesis[J]. Biochem Biophys Acta, 2015, 1852(4):651-657.
[2] Souroujon MC, Brenner T, Fuchs S. Development of novel therapies for MG:studies in animal models [J]. Autoimmunity, 2010, 43(5-6):446-460.
[3] Baggi F, Annoni A, Ubiali F, et al. Breakdown of tolerance to a self-peptide of acetylcholine receptor alpha-subunit induces experimental myasthenia gravis in rats[J]. J Immunol, 2004, 172(4):2697-2703.
[4] Diehl SA, Schmidlin H, Nagasawa M, et al. IL-6 triggers IL-21 production by human CD4+ T cells to drive STAT3-dependent plasma cell differentiation in B cells[J]. Immunol Cell Biol, 2012, 90(8):802-811.
[5] Aricha R, Mizrachi K, Fuchs S, et al. Blocking of IL-6 suppresses experimental autoimmune myasthenia gravis[J]. J Autoimmun, 2011, 36(2):135-141.
[6] Li WQ, Dehnade F, Zafarullah M. Oncostatin M-induced matrix metalloproteinase and tissue inhibitor of metalloproteinase-3 genes expression in chondrocytes requires janus kinase/STAT signaling pathway[J]. J Immunol, 2001, 166(5):3491-3498.
[7] 刘莹,李晓丽,徐华,等. 小剂量阿托伐他汀对实验性自身免疫性重症肌无力大鼠的治疗作用[J]. 山东大学学报(医学版),2012, 50(7):26-31. LIU Ying, LI Xiaoli, XU Hua, et al. Effects of lower dose of atorvastatin on experimental autoimmune myasthenia gravis in rats[J]. Journal of Shandong University(Health Sciences), 2012, 50(7):26-31.
[8] Park JS, Lee J, Lim MA, et al. JAK2-STAT3 blockade by AG490 suppresses autoimmune arthritis in mice via reciprocal regulation of regulatory T Cells and Th17 cells[J]. J Immunol, 2014, 192(9):4417-4424.
[9] Davoodi-Semiromi A, Hassanzadeh A, Wasserfall CH, et al. Tyrphostin AG490 agent modestly but significantly prevents onset of type 1 in NOD mouse; implication of immunologic and metabolic effects of a Jak-Stat pathway inhibitor[J]. J Clin Immunol, 2012, 32(5):1038-1047.
[10] Dienz O, Eaton SM, Bond JP, et al. The induction of antibody production by IL-6 is indirectly mediated by IL-21 produced by CD4+ T cells[J]. J Exp Med, 2009, 206(1):69-78.
[11] Ghoreschi K, Laurence A, Yang XP, et al. Generation of pathogenic TH 17 cells in the absence of TGF-β 2 signalling[J]. Nature, 2010, 467(7318):967-971.
[12] 王志强,张志坚,吴立坚,等. 重症肌无力患者外周血单个核细胞TNF-α和IL-6水平在疾病转归中的动态变化[J]. 中国神经免疫学和神经病学杂志, 2009, 16(2):90-93. WANG Zhiqiang, ZHANG Zhijian, WU Lijian, et al. The dynamic changes of tumor necrosis factor-α and interleukin-6 in peripheral blood mononuclear cells in patients with myasthenia gravis[J]. Clin J Neuroimmunol & Neurol, 2009, 16(2):90-93.
[13] Seo IA, Lee HK, Shin YK, et al. Janus kinase 2 inhibitor AG490 inhibits the STAT3 signaling pathway by suppressing protein translation of gp130[J]. Korean J Physiol Pharmacol, 2009, 13(2):131-138.
[14] Avery DT, Deenick EK, Ma CS, et al. B cell-intrinsic signaling through IL-21 receptor and STAT3 is required for establishing long-lived antibody responses in humans[J]. J Exp Med, 2010,207(1):155-171.
[15] Niu X, He D, Zhang X, et al. IL-21 regulates Th17 cells in rheumatoid arthritis[J]. Hum Immunol, 2010, 71(4):334-341.
[16] Costanzo A, Chimenti MS, Botti E, et al. IL-21 in the pathogenesis and treatment of skin diseases[J]. J Dermatol Sci, 2010, 60(2):61-66.
[17] Zhang M, Zhou Y, Guo J, et al. Thymic TFH cells involved in the pathogenesis of myasthenia gravis with thymoma[J]. Exp Neurol, 2014, 254:200-205. doi:10.1016/j.expneurol.2014.01.024.
[18] Davis ID, Skak K, Smyth MJ, et al. Interleukin-21 signaling:functions in cancer and autoimmunity [J]. Clin Cancer Res, 2007, 13(23):6926-6932.
[19] Kuchen S, Robbins R, Sims GP, et al. Essential role of IL-21 in B cell activation, expansion, and plasma cell generation during CD4+ T cell-B cell collaboration [J]. J Immunol, 2007, 179(9):5886-5896.
[20] Diehl SA, Schmidlin H, Nagasawa M, et al. STAT3-mediated up-regulation of BLIMP1 is coordinated with BCL6 down-regulation to control human plasma cell differentiation[J]. J Immunol, 2008,180(7):4805-4815.
[21] Lee SK, Rigby RJ, Zotos D, et al. B cell priming for extrafollicular antibody responses requires Bcl-6 expression by T cells[J]. J Exp Med, 2011, 208(7):1377-1388.
[22] Tuzun E, Allman W, Ulusoy C, et al. Novel animal models of acetylcholine receptor antibody-related myasthenia gravis[J]. Ann N Y Acad Sci, 2012, 1274:133-139. doi:10.1111/j.1749-6632.2012.06773.x.
[23] Huda R, Tuzun E, Christadoss P. Complement C2 siRNA mediated therapy of myasthenia gravis in mice[J]. J Autoimmun, 2013, 42:94-104. doi:10.1016/j.jaut.2013.01.003.
[24] Kusner LL, Kaminski HJ. The role of complement in experimental autoimmune myasthenia gravis[J]. Ann N Y Acad Sci, 2012, 1274(1):127-132.
[25] Huda R, Strait RT, Tuzun E, et al. IgG1 deficiency exacerbates experimental autoimmune myasthenia gravis in BALB/c mice[J]. J Neuroimmunol, 2015, 281:68-72. doi:10.1016/j.jneuroim.2015.03.004.
[1] 李秀华, 李晓丽, 段瑞生, 朱梅佳, 曹莉莉, 李衍滨, 王思, 岳龙涛, 马庆海, 刘菲. 1,25(OH)2D3诱导实验性自身免疫性重症肌无力大鼠免疫耐受的机制[J]. 山东大学学报（医学版）, 2015, 53(8): 5-10.
[2] 朱丽华, 赵琳琳, 李盖. 靶向沉默IL-6R基因对胃癌细胞增殖的影响[J]. 山东大学学报（医学版）, 2014, 52(S1): 22-23.
Viewed
Full text


Abstract

Cited
  Shared   
  Discussed   
No Suggested Reading articles found!
版权所有 © 2018 《山东大学学报(医学版)》编辑部　
地址:山东大学科技期刊社（济南市历城区山大南路27号山东大学中心校区明德楼B座721室） 电话: 0531-88366918 E-mail: xbyxb@sdu.edu.cn
本系统由北京玛格泰克科技发展有限公司设计开发