年轻慢性乙肝患者越早治疗越有效清除病毒

肝胆速递

Earlier treatment for young patients with chronic hepatitis B more effective in clearing virus
年轻慢性乙肝患者越早治疗越有效清除病毒

肝胆速递：该研究对传统指南发出挑战（慢性携带无需治疗），但有待进一步证实


http://medicalxpress.com/news/2012-09-earlier-treatment-young-patients-chronic.html

September 6, 2012 in Diseases, Conditions, Syndromes

Scientists from A*STAR's Singapore Institute for Clinical Sciences (SICS), together with clinical collaborators from London , discovered for the first time that children and young patients with chronic Hepatitis B Virus infection (HBV carriers) do have a protective immune response, contrary to current belief, and hence can be more suitable treatment candidates than previously considered.

This discovery by the team of scientists led by Professor Antonio Bertoletti, programme director and research director of the infection and immunity programme at SICS, could lead to a paradigm shift in the current treatment of patients with chronic HBV. The findings were published in Gastroenterology on 1st September. Current guidelines from international liver associations recommend delaying therapy until HBV carriers show clear signs of active liver disease, which generally appear after the age of 30 . This is based on two assumptions. One, young patients are unable to react to treatment because they are immune-tolerant to the virus. This means that there is no protective immune response in their body to help them get rid of the virus, and therefore, they will not run the risk of liver damage or inflammation. Two, HBV infection is largely harmless in HBV carriers until active liver disease is apparent. However, Professor Bertoletti and his team showed that young patients are not immune tolerant as they posses HBV-specific T cells with the ability to produce distinct antiviral cytokines that help the body fight against HBV. They also showed that the longer a patient is left untreated, the less effective their immune system becomes against HBV and the less able the patient will be able to clear the virus from their body even when they receive treatment. The scientists demonstrated that the presence of HBV in the body over a long period of time is harmful to the patient due to repeated activation of T-cells which induces a progressive state of T-cell exhaustion, a state of immune system dysfunction that prevents optimal control of the infection and clearance of the virus from the body. Thus, young patients produce an immune response against HBV which is less compromised than that in older patients. Professor Bertoletti said, "Young patients infected with HBV are most at risk of developing chronic HBV but current guidelines mean that they are also the least likely to be treated. However, our findings suggest that it might be better to start treatment early as young people with their stronger immune system, respond better to treatment and are more able to clear the virus." Prof Judith Swain, Executive Director of SICS, said, "These findings may change the way treatment is applied to patients with HBV in hospitals in Singapore and throughout the world. This is a fine example of how clinicians, physician scientists, and scientists work together to improve healthcare for the public."
More information: The paper can be accessed at www.gastrojournal.… 0-2/abstract
Journal reference: Gastroenterology search and more info website
Provided by Agency for Science, Technology and Research (A*STAR), Singapore

肝胆速递

早期治疗对于年轻的患者与慢性肝炎乙在清除病毒年9月6，2012年在疾病条件，辨证分型的科学家从A * STAR的新加坡研究所临床科学（SICS），连同临床合作者从伦敦，第一次发现更有效慢性B型肝炎病毒感染（乙肝病毒携带者）的儿童和青少年患者做保护性免疫反应，目前认为的相反，因此可以比以前认为的更适合的治疗候选人。

这的发现科学家领导的团队由的安东尼奥贝托列提教授，项目总监和研究总监在SICS的感染和免疫程序，可能会导致慢性乙肝患者目前的治疗模式的转变。胃肠病学的研究结果发表在9月1日。国际肝组织的目前的指导方针建议推迟治疗，直到乙肝病毒携带者活动性肝病，这一般出现在30岁后表现出明显的迹象。这是基于两个假设。一，年轻患者无法对治疗做出反应，因为他们的免疫耐受的病毒。这意味着，有没有在自己的身体保护性的免疫反应，以帮助他们摆脱病毒的，因此，他们将无法运行的风险，肝损伤或炎症。二，HBV感染是乙肝病毒携带者在很大程度上是无害的，直到活动性肝病是明显的。然而，教授贝托列提的和他的团队发现，年轻患者的免疫耐受，因为他们有足够的能力产生明显的抗病毒细胞因子，帮助身体对抗HBV HBV特异性T细胞。他们还发现，病人没有得到及时治疗，效果较差，他们的免疫系统变得对HBV和能力较差的病人会从他们身上能清除病毒，甚至当他们接受治疗。科学家证明，在很长一段时间的存在下，在体内的HBV是有害的病人由于重复激活T-细胞诱导T细胞耗竭累进状态，免疫系统功能障碍的状态下，防止最优从体内清除病毒的感染和控制。因此，年轻患者对乙肝病毒产生免疫反应，这是受到比在老年患者中。贝托列提教授说，“年轻患者感染乙肝病毒是最有可能发展成慢性乙肝病毒，但目前的指导方针的意思是，他们也是最有可能被视为然而，我们的研究结果表明，它可能是更好的年轻人开始早期治疗他们更强大的免疫系统，更好地应对治疗，更能够清除病毒。“ ，执行董事SICS教授朱迪思·斯温说，“这些研究结果可能会改变的方式处理，适用于在新加坡和世界各地的乙肝患者在医院的医生，医生科学家，和科学家一起工作，这是一个很好的例子。医疗水平的提高为市民服务。“更多信息：本文可以访问www.gastrojournal的.... 0-2/abstract的参考文献：胃肠病学搜索和更多的网站提供的科学，技术和研究局（A * STAR），新加坡

肝胆速递

http://www.sciencedirect.com/science/article/pii/S0016508512008402
Preserved T-Cell Function in Children and Young Adults With Immune-Tolerant Chronic Hepatitis B

    Patrick T.F. Kennedy⁎,
    Elena Sandalova‡,
    Juandy Jo‡,
    Upkar Gill⁎,
    Ines Ushiro–Lumb⁎,
    Anthony T. Tan‡,
    Sandhia Naik⁎,
    Graham R. Foster⁎,
    Antonio Bertoletti‡, §, ∥, Corresponding author contact information, E-mail the corresponding author

    ⁎ Institute of Cell and Molecular Science, Barts and The London School of Medicine & Dentistry, London, England
    ‡ Infection & Immunity Program, Singapore Institute for Clinical Sciences, A*STAR, Singapore
    § Program Emerging Viral Diseases, Duke-NUS Graduate Medical School, Singapore, Singapore
    ∥ Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

    http://dx.doi.org/10.1053/j.gastro.2012.06.009

Background & Aims

Chronic hepatitis B (CHB) infection acquired perinatally or in early childhood has been associated with a prolonged phase of immune tolerance from viral exposure into early adulthood. The immune-tolerant phase of the disease is characterized by high levels of hepatitis B virus (HBV) DNA and normal liver biochemistry, with minimal or no fibrosis. We investigated whether the age of patients with CHB affects their antiviral immunity and whether children and young adults have a veritable state of immunologic tolerance.
Methods

We isolated T cells from different age groups of patients with CHB and used flow cytometric methods to measure production of effector and inflammatory cytokines (interferon, tumor necrosis factor, interleukin [IL]-17A, IL-22, and IL-8), T-helper (Th)2 cytokines (IL-10, IL-4), Th1 cytokines (IL-2 and IL-21), and the CC chemokine CCL3 (MIP-1). We also measured markers of T-cell exhaustion or inhibition (PD-1, LAG-3, TIM3, LAIR-1, and CTLA-4) and HBV-specific T cells.
Results

Young patients with CHB have a Th1-cell cytokine profile and a partial profile of T-cell exhaustion. Direct quantification of the HBV-specific T-cell response showed that young patients with CHB have more HBV-specific T cells with the ability to proliferate and produce cytokines than adult patients with CHB.
Conclusions

HBV infection in younger patients is not associated with an immune profile of T-cell tolerance. On the contrary, children and young adults with chronic HBV infection have an HBV-specific immune profile that is less compromised than that observed in older patients.

肝胆速递

Preserved T-细胞功能的免疫耐受慢性乙型肝炎的儿童和年轻成人

    帕特里克T.F.肯尼迪⁎，
    埃琳娜Sandalova‡
    Juandy乔‡
    Upkar吉尔⁎，
    伊内斯USHIRO兰布⁎，
    安东尼·T.谭‡，
    Sandhia奈克⁎，
    格雷厄姆R.福斯特⁎
    安东尼奥贝托列提‡，§，∥，通讯作者的联系信息，E-mail的通讯作者

    ⁎研究所细胞与分子科学学院，巴兹与伦敦，英国伦敦医学与牙科学院
    ‡“感染与免疫计划，新加坡临床科学研究所，A * STAR，新加坡
    §计划新出现的病毒性传染病，杜克 - 国大医学研究生院，新加坡，新加坡
    ∥医学系，新加坡国立大学杨潞龄医学院，新加坡

    http://dx.doi.org/10.1053/j.gastro.2012.06.009

背景与目的

慢性乙型肝炎（CHB）感染围产期获得的或在儿童早期一直伴随着长期的免疫耐受阶段，从病毒接触到成年早期。免疫耐受期的疾病的特征在于，高浓度的B型肝炎病毒（HBV）DNA和正常肝生物化学，最小或无纤维化。我们调查的慢性乙型肝炎患者的年龄是否会影响其抗病毒免疫的儿童和年轻人是否有一个名副其实的免疫耐受状态。
方法

我们从不同年龄组的慢性乙型肝炎患者分离出的T细胞，并用流式细胞仪的方法来衡量生产效应和炎性细胞因子（干扰素，肿瘤坏死因子，白细胞介素IL-17A，IL-22，IL-8），T -辅助（Th）细胞因子（IL-10，IL-4），Th1型细胞因子（IL-2和IL-21），和CC趋化因子CCL3（MIP-1）。我们还测量了T细胞的耗竭或抑制（PD-1，LAG-3，TIM3，LAIR-1，和CTLA-4）和HBV特异性T细胞的标志物。
结果

年轻的慢性乙型肝炎患者的Th1细胞的细胞因子和T-细胞耗竭的部分档案。直接定量分析表明，年轻的慢性乙型肝炎患者的HBV特异性T细胞反应有更多HBV特异性T细胞增殖的能力比成人慢性乙型肝炎患者细胞因子和生产。
结论

年轻患者的HBV感染的免疫T细胞耐受的档案是不相关的。相反，儿童和年轻成人慢性HBV感染的HBV特异性免疫档，比年龄较大的患者中观察到的损害较小。

咬牙硬挺

感谢分享，楼主辛苦

StephenW

回复 咬牙硬挺 的帖子

这实际上是一个非常显着意义的论文。它推翻了当前的免疫耐受性的认识，同时也提出了许多新的问题。

把握当下

第一篇论文说hbv在身体里时间越长，将发生反复的t细胞激活，导致t细胞耗竭，即免疫系统出现问题，因此其实年轻人的免疫系统比年长者更好。从这个意义上说治疗指南有不足。

问题是什么样的（携带）年轻人应该治疗？在我所看到的医生观点中，只见老王提过这个问题，他提出可以进行试探性治疗，并且确实有携带拉米金牌的例子。虽然只是个例，或可佐证。

StephenW

回复 把握当下 的帖子

"第一篇论文说hbv在身体里时间越长，将发生反复的t细胞激活，导致t细胞耗竭，即免疫系统出现问题，因此其实年轻人的免疫系统比年长者更好。从这个意义上说治疗指南有不足。"
这是一个重要的结论,
但也有其他同样重要的结论:


This is the comment from two scientists:

"In conclusion, the interesting study by Kennedy et al details two important, view-changing observations concerning tolerance during CHB. First, there is no inherent age-associated induction of tolerance in children and young adults with CHB. Second, where HBV-specific T-cell response were not previously thought to exist, such responses do exist, and were consistently observed through repeated follow-up analyses. Even the breadth of viral antigens targeted by HBV-specific T cells during the tolerant phase of CHB was surprisingly broad, and counters the prevailing opinion that immune recognition of HBV is somehow completely averted in certain individuals."


这是两位科学家的评论：

“最后，肯尼迪等细节两个重要的，改变视图意见耐性CHB的有趣的研究。首先，有没有内在的与年龄有关的慢性乙型肝炎的儿童和年轻成人耐受诱导。二，HBV-T-细胞反应没有以前想象的存在，确实存在这样的回答，并持续观察到通过反复的后续分析。，即使HBV特异性T细胞的耐受期慢性乙型肝炎病毒抗原有针对性的广度是令人惊讶的广泛的，计数器普遍认为HBV的免疫识别某种方式完全避免了某些人。“

咬牙硬挺

携带者治疗还只是探索，或许以后会写入指南，也许永远不会。越研究越发现我们了解的太少

把握当下

回复 StephenW 的帖子

他们的结论很惊人：所谓早期免疫耐受根本不存在。

确实有一些这样的迹象，例如一些小孩打干扰很容易好转，个别携带治疗也能好转


问题是，这些t细胞能完全代表hbv特定的免疫系统吗？他们目前认为是（Even the breadth of viral antigens targeted by HBV-specific T cells during the tolerant phase of CHB was surprisingly broad）


按照他们的思路来说应该一发现hbv就立刻治疗（不管肝功能），如果不治疗随着时间流逝免疫系统只会变得更弱
但实际上，有些人的免疫系统却更强了？例如alt爆发？这个算合适的反例吗？