慢性乙型肝炎的免疫发病机制与免疫评估 Immunopathogenesis and immunological assessment of chronic hepatitis B 吴超 Chao Wu Department of Infectious Diseases Nanjing Drum Tower Hospital Nanjing University Medical School
Outline Immunopathogenesis of chronic hepatitis B Immunological assessment of chronic hepatitis B Novel immune-based therapeutic strategies for CHB
Natural history of hepatitis B virus infection The age of infection largely dictates the type and level of the immune response to acute HBV infection and the subsequent natural history of CHB. Gish RG, et al. Antiviral Res 2015;121:47-58.
Natural history of hepatitis B virus infection Chronic HBV infection is a dynamic process. The natural history of chronic HBV infection can be schematically divided into five phases. Trépo C, et al. Lancet 2014;384(9959):2053-63.
Characteristics of immunities in different 自然病程 natural course of 慢性乙肝感染 CHB infection Significant differences in host innate and adaptive immunities in different natural course of CHB infection. Zhang Z, et al. J Gastroenterol Hepatol 2012;27(2):223-30.
先天免疫 Innate immunity in HBV infection NK cells, NKT cells, DC cells, Kupffer cells and even hepatocytes play important roles in defense against HBV. 解 ffer) 细胞 适应性 Han Q, et al. Semin Immunopathol 2013; 35:23-38.
NK cells 慢性乙肝患者干扰素分泌功能受损 Impaired capacity to produce γ 干扰素 IFN-γ in CHB patients. Peppa D, et al. PLoS Pathog 2010;6(12):e1001227.
DCs DCs frequencies are reduced in chronic HBV patients. The expression of 细胞表面分子 cell surface molecules HLA-DR, CD83, CD86 and CD80 decrease with chronic HBV infection. Impaired DCs function leads to inadequate 乙肝 T 细胞应答 T cell response to HBV. Sun HH, et al. J Med Virol 2016;88(1):13-20.
适应性免疫 Adaptive immunity against HBV CD4 T cells produce 细胞因子 cytokines and required for the efficient development CTL. CD8 T cells clear HBV-infected hepatocytes through 细胞溶解机制 cytolytic and 非细胞溶解机制 noncytolytic mechanisms. B cells antibody production neutralizes free 乙肝病毒颗粒 HBV viral particles.
抗病毒适应性免疫应答 Antiviral adaptive immune response in CHB Tan A, et al. Cold Spring Harb Perspect Med 2015;5:a021428
Extended T 细胞家族 T-cell family in HBV infection Treg cells suppress HBV-specific T-cell functions & have an 抗炎作用 anti-inflammatory effect. Th17 cells has a 促炎作用 proinflammatory effect. Tan A, et al. Cold Spring Harb Perspect Med 2015;5:a021428
Impaired adaptive immune response in CHB 乙肝特异性 HBV-specific CD8+ T-cell response extremely weak. CD4+ T-cells weak, 单特异性 monospecific, dysfunctional. Highly express inhibitory molecules like PD-1, CTLA-4, TIM-3 on T cells. Bertoletti A,et al. Gut 2012;61:1754 1764. Tan A, et al. Cold Spring Harb Perspect Med 2015;5:a021428
Outline Immunopathogenesis of chronic hepatitis B Immunological assessment of chronic hepatitis B Novel immune-based therapeutic strategies for CHB
Question Background 治疗前 : 治疗时机难以判断和把握 哪些患者需要治疗? 传统指标 : ALT HBV-DNA HBeAg HBsAg 何时开始治疗? 治疗中 : 抗病毒治疗时间长,serum conversion 血清转换率低 如何评估疗效? 是否有其他抗病毒方案? 治疗后 :cccdna 难以清除,drug discontinuance 停药后易复发 停药时机如何把握? 新指标? 新方法? 新思路?
4P Medicine predictive personalized preventive Participatory ( 预测 个性化 预防 参与 )
关于乙肝抗病毒治疗前评估 高 低 长 短 活 不 大
Immunological assessment of CHB Before antiviral treatment During antiviral treatment Post antiviral treatment
Before 抗病毒治疗 antiviral treatment qhbsag 乙型肝炎表面抗原定性测定 基线血清乙肝表面抗原 Baseline serum HBsAg level was an independent predictor Of 治疗后 post-treatment 乙肝复发 HBV relapse after NAs treatment. Yao CC, et al. J Gastroenterol Hepatol 2015;30(5):918-24.
Before antiviral treatment GGT Baseline 谷氨酰转移酶 GGT levels as a candidate predictor of e 型乙肝抗原血清转换 HBeAg seroconversion following NA therapy. Huang R, et al. World J Gastroenterol 2015; 21(34): 9957-9965.
Before antiviral treatment Breg Bregs were significantly elevated in the HBeAg positive CHB. Unpublised data
Before antiviral treatment NK cells CD56 bright NK cells were increased in the HBeAg positive CHB. Unpublished data
Before antiviral treatment IP-10 Higher pre-treatment IP-10 levels are associated with an increased probability of HBeAg loss after 聚乙二醇化干扰素 PegIFN therapy. Sonneveld MJ, et al. J Hepatol 2013;58(5):898-903.
During antiviral treatment IL-21 High serum IL-21 levels after 12 weeks of antiviral therapy predict HBeAg seroconversion in CHB during 替比弗丁 telbivudine therapy for HBeAg-positive CHB. Ma SW, et al. J Hepatol 2012;56(4):775-81.
During antiviral treatment anti-hbc In the 聚乙二醇化干扰素 PEG-IFN and NAs cohort, patients with HBeAg seroconversion had higher 乙型肝炎核心抗体 anti-hbc level than those without HBeAg seroconversion. PEG-IFN cohort NAs cohort Fan R, et al. Gut 2016;65:313-320.
During antiviral treatment PD-1 The rapid decrease of PD-1 expression on 外周血 peripheral CD8+ T cells after ETV Treatment may be used as a predictive index for HBeAg seroconversion. Xia J, et al. Zhonghua Gan Zang Bing Za Zhi 2011;19(2):93-7.
During antiviral treatment NKT NKT cell frequency significantly reduced in well-responders at week 12 of 替比弗丁 telbivudine therapy compared to baseline. Diao H, et al. Immunol Lett 2014;160(1):65-71.
Post antiviral treatment qhbsag HBeAg (+) HBeAg (-) HBsAg level at the end of treatment was an independent predictor for HBsAg loss 抗原阳性 HBeAg-positive and HBeAg-negative patients after stopping 拉米夫定 lamivudine treat Chen CH, et al. J Hepatol 2014;61(3):515-22.
Post antiviral treatment qhbsag Higher serum HBsAg at the end of treatment was associated with higher risk of 病毒学复发 virological relapse. Liang Y, et al. Aliment Pharmacol Ther 2011; 34: 344-352.
筛选免疫活化患者区分患者免疫状态指导药物选择预测治疗疗效指导药物调整把握停药时机CHB 患者免疫发病机制及 immunity assessment 免疫状态评估 小结 T 细胞亚群比例及其 PD-1 表达 CD56brightNK 细胞亚群比例 NKT 细胞调节性 B 细胞亚群比例 Serum cytokines 血清细胞因子 (IL-10 IP-10) 红细胞体积分布宽度 (RDW) 谷氨酰转肽酶 (GGT) HBeAg/HBsAg 定量 免疫负性调节 探讨 CHB 免疫发病机制 建立免疫评估体系 Immune impairment 免疫损伤指标 治疗前的免疫评估 治疗中的免疫评估
Outline Immunopathogenesis of chronic hepatitis B Immunological assessment of chronic hepatitis B Novel immune-based therapeutic strategies for CHB
Approval of hepatitis B therapeutics
Potential new therapies for chronic hepatitis B Block TM, et al. Antiviral Res 2015;121:69-81.
Novel immune-based therapeutic strategies for CHB Tan A, et al. Cold Spring Harb Perspect Med 2015;5:a021428.
Immunotherapeutic interventions in development for the management of CHB Arrowhead RNA interference ARC-520 Brahmania M, et al. Lancet Infect Dis 2016; 16: e10-21.
Therapeutics in development for the management of chronic HBV infection T.M. Block et al. / Antiviral Research 121 (2015) 69 81
Summary The immune responses to HBV are 介导 mediated through complex interactions between the 先天免疫与适应性免疫系统的复相互作用 innate immune and adaptive immune systems. 免疫状态评估 Immunological assessment are important for CHB before, during and post antiviral treatment. The emergence of activity in developing novel agents targeting 宿主免疫应答 host immune response may hold promise for cure of HBV.