慢性乙型肝炎的免疫治疗研究进展*

doi:10.3969/j.issn.1672-5069.2016.04.032

Abstract

Abstract: There are two categories of antiviral agents that have been commonly used in treatment of patients with chronic hepatitis B,e.g. interferons and nucleos（t）ide analogues. Most patients fail to obtain eradication of HBV even receiving a long-term treatment. Disease control and viral clearance depend on the host’s immune responses,which is closely associated with specific-immunity,especially cellular immunity. Strategies of immunotherapies to boost or restore the virus-specific immune response of patients with chronic hepatitis B virus infection have been proposed for curing persistent infections. Currently,researches on immunotherapies focused on Toll-like receptors（TLR） agonists,negative immunomodulatory molecules of cytotoxic T lymphocyte（CTL）,CTL agonists,therapeutic vaccinations,specific T cell receptor（TCR） transgenic technology,chimeric antigen receptor T （CAR-T）cells,small molecule,etc. This review summarizes the recent progress in the above researches.

Key words: Chronic hepatitis B, Immune therapy, Progress

Qiao Yan, Xu Dongping, Li Jin. Immuno-therapy for chronic hepatitis B[J]. JOURNAL OF PRACTICAL HEPATOLOGY, 2016, 19(4): 493-496.

References

[1] You CR,Lee SW,Jang JW,et al. Update on hepatitis B virus infection. World J Gastroenterol,2014,20（37）:13293-13305.
[2] Liang X,Bi S,Yang W,et al,Epidemiological serosurvey of hepatitis B in China-declining HBV prevalence due to hepatitis B vaccination. Vaccine,2009,27（47）:6550-6557.
[3] Broering R,Lu M,Schlaak JF. Role of Toll-like receptors in liver health and disease. Clin Sci （Lond）,2011,121（10）:415-426.
[4] Guo H,Jiang D,Ma D,et al. Activation of pattern recognition receptor-mediated innate immunity inhibits the replication of hepatitis B virus in human hepatocyte-derived cells. J Virol,2009,83（2）:847-858.
[5] Lanford RE,Guerra B,Chavez D,et al. GS-9620,an oral agonist of Toll-like receptor-7,induces prolonged suppression of hepatitis B virus in chronically infected chimpanzees. Gastroenterology,2013,144:1508-1517.
[6] Lopatin U,Wolfgang G,Tumas D,et al. Safety, pharmacokinetics and pharmacodynamics of GS-9620,an oral Toll-like receptor 7 agonist. Antivir Ther,2013,18:409-418.
[7] Gane EJ,Lim YS,Gordon SC. et al. The oral toll-like receptor-7 agonist gs-9620 in patients with chronic hepatitis B virus infection. Hepatology,2015,63,320-328.
[8] Sablan BP,Kim DJ,Barzaga NG,et al. Demonstration of safety and enhanced seroprotection against hepatitis B with investigational HBsAg-1018 ISS vaccine compared to a licensed hepatitis B vaccine. Vaccine,2012,30:2689-2696.
[9] Halperin SA,Ward B,Cooper C,et al. Comparison of safety and immunogenicity of two doses of investigational hepatitis B virus surface antigen co-administered with an immunostimulatory phosphorothioate oligodeoxyri-bonucleotide and three doses of a licensed hepatitis B vaccine in healthy adults 18-55 years of age. Vaccine,2012,30:2556-2563.
[10] Zhang E,Lu M. Toll-like receptor（TLR）-mediated innate immune responses in the control of hepatitis B virus （HBV） infection. Med Microbiol Immunol,2015,204:11-20.
[11] Kapoor R,Kottilil S. Strategies to eliminate HBV infection. Fut Virol,2014,9（6）:565-585.
[12] Peng GP,Li SP,Wu W,et al. PD-1 upregulation is associated with HBV-specific T cell dysfunction in chronic hepatitis B patients. Mol Immunol,2008,45:963-970.
[13] Tzeng HT,Tsai HF,Liao HJ,et al. PD-1 blockage reverses immune dysfunction and hepatitis B viral persistence in a mouse animal model. PLoS One,2012,7（6）:e39179.
[14] Yu Y,Wu H,Tang Z,et al. CTLA4 silencing with siRNA promotes deviation of Th1/Th2 in chronic hepatitis B patients. Cell Mol Immunol,2009,6（2）:123-127.
[15] Schurich A,Khanna P,Lopes AR,et al. Role of the coinhibitory receptor cytotoxic T lymphocyte antigen-4 on apoptosis-Prone CD8 T cells in persistent hepatitis B virus infection. Hepatology,2011,53（5）:1494-1503.
[16] Wu W,Shi Y,Li S,et al. Blockade of Tim-3 signaling restores the virus-specific CD8 + T-cell response in patients with chronic hepatitis B. Eur J Immunol,2012,42（5）:1180-1191.
[17] Nebbia G,Peppa D,Schurich A,et al. Upregulation of the Tim-3/galectin-9 pathway of T cell exhaustion in chronic hepatitis B virus infection . PLoS One,2012,7（10）:647-648.
[18] Ju Y,Hou N,Meng J,et al. T cell immunoglobulin and mucin-domain-containing molecule-3 （Tim-3） mediates natural killer cell suppression in chronic hepatitis B. J Hepatol,2010,52（3）:322-329.
[19] 童新灯,李敏,胡国信,等. 慢性乙型肝炎患者外周血IL-7与细胞免疫的关系. 中国热带医学,2014,8:912-914.
[20] Mackall CL,Fry TJ,Gress RE. Harnessing the biology of IL-7 for therapeutic application. Nat Rev Immunol,2011,11（5）:330-343.
[21] Publicover J,Goodsell A,Nishimura S,et al. IL-21 is pivotal in determining age-dependent effectiveness of immune responses in a mouse model of human hepatitis B. J Clin Invest,2011,121（3）:1154-1162.
[22] Gaggar A,Coeshott C,Apelian D,et al. Safety, tolerability and immunogenicity of GS-4774,a hepatitis B virus-specific therapeutic vaccine,in healthy subjects:a randomized study. Vaccine,2014,32:4925-4931.
[23] Martin P,Dubois C,Jacquier E,et al. TG1050,a viral-vector based immunotherapeutic designed to treat chronic hepatitis B induces immunoresponses with properties similar to those displayed by HBV resolving patients and has an early antiviral effect in a HBV tolerant model. Hepatology,2013,57:224-233.
[24] Spellman M,Martin JT. Treatment of chronic hepatitis B infection with DV-601,a therapeutic vaccine. J Hepatol,2011,54（Suppl 1）: S302.
[25] Lobaina Y,Hardtke S,Wedemeyer H,et al. In vitro stimulation with HBV therapeutic vaccine candidate Nasvac activates B and T cells from chronic hepatitis B patients and healthy donors. Mol Immunol,2015,63:320-327.
[26] Scott-Algara D,Mancini-Bourgine M,Fontaine H,et al. Changes to the natural killer cell repertoire after therapeutic hepatitis B DNA vaccination. PLoS One,2010,5（1）:e8761.
[27] Yang SH,Lee CG,Park SH,et al. Correlation of antiviral T-cell responses with suppression of viral rebound in chronic hepatitis B carriers:a proof-of-concept study. Gene Ther,2006,13（14）:1110-1117.
[28] Yang FQ,Yu YY,Wang GQ,et al. A pilot randomized controlled trial of dual-plasmid HBV DNA vaccine mediated by in vivo electroporation in chronic hepatitis B patients under lamivudine chemotherapy. J Viral Hepat,2012,19（8）:581-593.
[29] Inchauspé G1,Michel ML. Vaccines and immunotherapies against hepatitis B and hepatitis C viruses. J Viral Hepat,2007,14（1）:97-103.
[30] Michel M L,Bourgine M,Fontaine H,et al. Therapeutic vaccines in treating chronic hepatitis B:the end of the beginning or the beginning of the end Mol Ther Nucl Acids,2015,204（1）:121-129.
[31] 吴静,王琳,刘妍,等. 转基因表达乙型肝炎病毒抗原特异性细胞毒性T淋巴细胞受体的研究. 细胞与分子免疫学杂志,2013,29（5）:453-487.
[32] Koh S,Shimasaki N,Suwanarusk R,et al. A practical approach to immunotherapy of hepatocellular carcinoma using T cells redirected against hepatitis B virus. Mol Ther Nucl Acids,2013,2（8）:e114.
[33] Qasim W,Brunetto M,Gehring AJ,et al. Immunotherapy of HCC metastases with autologous T cell receptor redirected T cells,targeting HBsAg in a liver transplant patient. J Hepatol,2015,62（2）:486491.
[34] Gill S,June CH. Going viral: chimeric antigen receptor T-cell therapy for hematological malignancies. Immunol Rev,2015,263（1）:6889.
[35] Bohne F,Chmielewski M,Ebert G,et al. T cells redirected against hepatitis B virus surface proteins eliminate infecdted hepatocytes. Gastroenterology,2008,134（1）:239-247.
[36] Sadelain M,Brentjens R,Riviere I. The basic principles of chimeric antigen receptor design. Cancer Disco,2013,3（4）: 388-398.
[37] 刘小燕,李朝品,王克霞. 多糖抗乙型肝炎病毒作用的研究进展. 中国病原生物学杂志,2014,9:845-851.
[38] 陈玉琴,吴群,张义翠,等. 阿德福韦酯联合香菇多糖治疗慢性乙型肝炎疗效观察. 医学理论与实践,2012,4:383-384.

Immuno-therapy for chronic hepatitis B

PDF (PC)

Knowledge

Abstract

Cite this article

share this article

References

Related Articles 15

Recommended Articles

Metrics

Comments

[1]	chronic hepatitis B Zhu Lingyun, Zhang Maohai Cui Shasha, et al.. Serum IL-12 and IL-18 levels as well as peripheral blood mononuclear cell FOXp3 in patients with [J]. Journal of Practical Hepatology, 2019, 22(6): 816-819.
[2]	patients with chronic hepatitis B Zhang Yingming, Shen Shuang, Tian Fei, et al.. Prediction of response to peginterferon alfa-2a by blood IFNL4 and IL-28B gene polymorphisms in [J]. Journal of Practical Hepatology, 2019, 22(6): 828-831.
[3]	Du Keye, Yang Dongliang, Liu Jia. Regulatory T cells in hepatitis B [J]. Journal of Practical Hepatology, 2019, 22(5): 613-616.
[4]	Gao Wei, Hou Yong. Diagnostic efficacy of hepatic fibrosis by liver stiffness measurement in patients with chronic hepatitis B [J]. Journal of Practical Hepatology, 2019, 22(5): 652-655.
[5]	Bai Yichun, Deng Jihong, Mei Xiaoping. Efficacy of peginterferon alfa-2b treatment and affecting response factors in patients with chronic hepatitis B [J]. JOURNAL OF PRACTICAL HEPATOLOGY, 2019, 22(4): 490-493.
[6]	Zhang Yafei, Ye Jun, Xie Qinxiu, et al. Difference in predicting efficacy of significant liver fibrosis by noninvasive liver fibrosis index in different hospitals [J]. JOURNAL OF PRACTICAL HEPATOLOGY, 2019, 22(4): 510-513.
[7]	Wang Baodan, Li Meng, Gao Yu. Predictive factors of response to interferon-α antiviral therapy in children with chronic hepatitis B [J]. JOURNAL OF PRACTICAL HEPATOLOGY, 2019, 22(3): 345-348.
[8]	Jiang Yi, Liu Bing. Comparison of clinical features and histopathological activity index between patients with chronic hepatitis B and chronic hepatitis C [J]. JOURNAL OF PRACTICAL HEPATOLOGY, 2019, 22(2): 188-191.
[9]	Hu Hulan, Zhu Mengfei, Shi Junping.. Non-alcoholic fatty liver disease with concurrent chronic hepatitis B: What’s the progress [J]. JOURNAL OF PRACTICAL HEPATOLOGY, 2019, 22(1): 149-152.
[10]	Wang Yaofeng.. Efficacy and safety of tenofovir in the treatment of patients with chronic hepatitis B [J]. JOURNAL OF PRACTICAL HEPATOLOGY, 2018, 21(6): 847-850.
[11]	Huang Chunming, Yang Zhan, Nie Yuqiang, et al.. Prediction of liver fibrosis by gamma-glutamyl-transpeptidase-to-platelet ratio in patients with chronic hepatitis B viral infection with normal serum transaminase levels [J]. JOURNAL OF PRACTICAL HEPATOLOGY, 2018, 21(6): 859-862.
[12]	Baoyan, Wang Yun, Xiang Xiaogang, et al.. Prognosis of patients with hepatocellular carcinoma and underlying hepatitis B An [J]. JOURNAL OF PRACTICAL HEPATOLOGY, 2018, 21(6): 924-927.
[13]	Zhou Zhiling, Yin Qian.. Forecasting hepatic activity index and liver fibrosis staging by serum golgiprotein-73 levels in individuals with chronic hepatitis B viral carriers [J]. JOURNAL OF PRACTICAL HEPATOLOGY, 2018, 21(5): 717-720.
[14]	Wang Fangfang, Zhang Guofan, Guo Chunxia, et al.. Clinical efficacy and safety of switching from entecavir to interferon-α in patients with hepatitis B [J]. JOURNAL OF PRACTICAL HEPATOLOGY, 2018, 21(5): 721-724.
[15]	Shi Luoming, Zhou Gengfa, Sun Donglin. Prediction of response in patients with low serum HBsAg level chronic hepatitis B receiving peginterferon-α-2a after nucleos(t)ide analogues treatment [J]. JOURNAL OF PRACTICAL HEPATOLOGY, 2018, 21(4): 565-568.