Abstract
摘要:根據世界衛生組織指出至今估計約有 2.4 億的慢性B 型肝炎病毒帶原者,在B 型肝炎疫苗推出30 年後,慢性B 型肝炎病毒感染仍然是全球公共衛生棘手的問題。在這些慢性B 型肝炎病毒帶原者,約四分之一的人最終將死於肝臟相關疾病,如肝癌或肝硬化。自從2000 年開始使用有效和安全的抗B型肝炎病毒療法,尤其是病毒逆轉錄酶抑制核苷(酸)類似物(Entecavir 或Tenofovir)能夠抑制病毒複製,然後降低50%肝臟相關死亡的風險相較於未接受治療者。儘管有這些令人印象深刻的成果,然而目前的抗B 型肝炎病毒療法仍然失敗清除B 型肝炎病毒的感染,使這些B 型肝炎病毒感染者需藉由長期並有可能終身接受抗病毒治療。因此,一個有限時期的治療,達到清除B 型肝炎病毒感染已成為生物醫學界的一大挑戰。要認識 B 型肝炎病毒帶原者保留剩餘的抗B 型肝炎病毒的免疫力是很重要的,所以約1%B 型肝炎病毒帶原者自發地清除B 型肝炎病毒。如何重新改編殘餘的抗B 型肝炎病毒的免疫力,以克服目前的治療療法相關的限制,並有效地清除B 型肝炎病毒是此計畫的主要目標。人類的免疫反應對抗B 型肝炎病毒有幾個獨特的功能:1. B 型肝炎病毒清除取決於年齡暴露,年齡越小越少;2. 隱身先天免疫反應特點是少量干擾素的誘導,仍然會造成有效的後天性免疫; 意味著由B 型肝病毒所引發的非傳統的先天免疫反應(可能是通過新穎的病毒病原相關分子模式,PAMPs,和免疫細胞上的不同模式辨識受體,PRRs); 3.腸道菌群可能在肝臟免疫力來對抗B 型肝炎病毒的作用中扮演重要的角色。利用免疫完整的小鼠模式(高壓注射B 型肝炎病毒的DNA,HDI-HBV),可以有效地再現人類B 型肝病毒反應的特點,我們提出以下四個子計畫。子計畫 1.先天淋巴樣細胞(尤其是自然殺手(NK)細胞)和它們在B 型肝炎病毒的PRR 打破耐受性。子計畫 2.先天髓樣細胞(特別是Kupffer 細胞)和它們在B 型肝炎病毒的PRR 建立耐受性。子計畫 3.腸道菌群在決定B 型肝炎病毒感染年齡依賴性的結果扮演重要的角色。主要計畫(子計畫4.) 重新改編先天性或後天性免疫中的B 型肝炎病毒帶原者的病毒清除:當前的限制和新的方法。在高壓注射 B 型肝炎病毒的DNA 小鼠模式中,可以有效控制以及全面性的分析從急性B 型肝炎病毒暴露到病毒清除或持續性的免疫機制。B 型肝炎病毒遺傳變異株或基因剔除小鼠品系,可在此HDI-HBV 小鼠模式中容易應用來解決此問題。最後,從小鼠模式的研究結果將在樹鼩慢性B 型肝炎病毒模式或臨床樣本中進行驗證,我們期待在未來能從B 型肝炎病毒感染患者中得知新的知識和新的免疫途徑導致B 型肝病毒的清除。
Abstract: Chronic hepatitis B virus infection remains a worldwide public health problem even 30 years after thelaunching of HBV vaccination, According to WHO there are still estimated 240 million chronic HBV carrierstoday. Among these carriers, about one quarter of them will eventually succumb to liver-related death such ashepatocellular carcinoma or cirrhosis. Effective and safe anti-HBV therapies become available since 2000,especially the viral reverse transcriptase inhibiting nucleos(t)ide analogs (Entecavir or Tenofovir) that cansuppress viral replication and then reduce the risk of liver-related death to 50% of that of the untreated.Despite of these impressive outcomes, current anti-HBV regimens fail to eliminate HBV infection bylong-term and possibly life-long antiviral therapy. Therefore a finite-period therapy to eradicate HBVinfection has emerged as a major unmet need and a challenge for biomedical community.It is important to realize that HBV carriers retain residual anti-HBV immunity, so about 1% of carriersspontaneously clear their HBV annually. How to reprogram the residual anti-HBV immunity, to overcome thelimitations associated with current treatment therapies, and to recovering efficiently to clear HBV are themain goals of this proposal. The human immune responses against HBV have several unique features: 1.HBV clearance depends on the age of exposures, the younger the less; 2. Stealthy innate immune responsescharacterized of little interferon induction but still leading to effective adaptive immunity; it implies anon-conventional innate immune responses triggered by HBV (likely through novel viralPathogen-Associated Molecular Patters, PAMPs, and cellular Pattern Recognition Receptors, PRRs); 3.Gut microbiota may play a role in liver immunity against HBV. By the use of immuno-competent mousemodels (the hydrodynamic injection of HBV DNAs, HDI-HBV) that can reliably reproduce these features inhuman HBV responses, we propose the following four sub-projects.Subproject 1. Innate lymphoid cells (especially Natural killer (NK) cells) and their PRRs in breakingtolerance to hepatitis B virus.Sub-project 2. Innate myeloid cells (especially Kupffer cells) and their PRRs in establishing tolerance tohepatitis B virus.Sub-project 3. Gut microbiota play a critical role in determining the age-dependent outcome of hepatitis Bvirus infectionMain project (subproject 4). Re-programming innate or adaptive immunity in HBV carriers for viralclearance: current limitations and new approaches.The HDI-HBV mouse models allow a controlled, detailed and comprehensive analysis of immunemechanisms from acute HBV exposure to HBV clearance or persistence. Genetic HBV mutants or geneknock-out mice strains can be easily applied in this HDI-HBV mouse models to resolve the issues. Ultimately,the findings from the mouse models will be validated in either the tree shrew chronic HBV model or in theclinical samples. We look forward to new knowledge and novel immune approaches leading to clearance ofHBV from CHB patients in the future.
Keyword(s)
B 型肝炎病毒帶原
腸道菌群
先天性免疫
先天性或後天性免疫
高壓注射Hepatitis B Virus Persistence
Gut microbiota
Innate immunity
Adaptive immunity
hydrodynamic injection