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
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. 作者: 肝胆速递 时间: 2012-9-8 01:19
"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."
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)
"按照他们的研究,免疫反应一直有" - agree.
"并且年龄小的反应应该更大" - disagree a little. In chronic hepatitis, after repeated unsuccessful attempts to clear the infection, HBV specific T cells become exhausted (increased expression of PD-1, programmed cell death protein 1) and epitope deletion. So it is the HBV specific T cell response that seems to become less effective.
"所以应该不能静止才对如果能解释这个问题,研究才能站住脚了" - Mechanisms of "quiescence":
Functional tolerance:
1 Suppression (Tregs)
2 Exhaustion (PD-1)
3 Deletion
4 Anergy
如果Mechanisms of "quiescence"正确,那么这个"quiescence" 就是免疫耐受,而不是像论文说的不存在:就算小孩感染病毒后各种免疫反应很好很多,只要当时不能解决病毒,终究会变成耐受;一些小孩长大后爆发急性肝炎确实打破了之前的“静止”
成年人感染后免疫反应足以解决病毒,因此大部分不会耐受
"论文说的免疫反应随着时间增加越来越弱的问题应该是指转变成耐受的这个过程:刚开始感染时,免疫有反应,但是免疫调动的能量很快被病毒耗竭了,就耐受了。其实是符合人们一直以来的认识的。" - 这点是比较复杂的. 对论文发表了评论的两位科学家(Velazquez & Grakoui)有不同的观点. 因为我不明白他们所说一切, 我只一知半解, 这是我的理解他们的观点:
1.这项新的研究发现,年纪更大T细胞更“耗竭” (In Chronic Hepatitis B patients, frequencies of CD8+ T cells displaying a PD-1 high/CD127 low 'exhausted' phenotype were actually found to increase with age, whereas HBV-specific interferon-gamma production decreased).
2.因此应该更早医疗.
但是:
1. 当年轻时, 病毒载量是非常高的. 因此, T细胞应该更“耗竭”!
2. 一个可能的解释(新的研究中没有研究) - 当年轻时,T细胞没有达到肝内受感染的肝细胞 (a migratory defect that could prevent functional HBV-specific T cells from gaining access to virus-infected hepatocytes.).
HBV specific CD8+ T cells are produced in the lymph system and must migrate to the liver to attack HBV infected liver cells.
HBV特异性CD8+ T细胞产生在淋巴系统, 需要迁移到肝脏攻击HBV感染的肝细胞。
"The authors also demonstrated that T-cell expression of the CC chemokine CCL3 (involved in the migration) was impaired in the immune tolerant cohort, compared with healthy control subjects and immune active CHB patients"
“作者还表明,在免疫耐受人群T-细胞表达CC趋化因子CCL3(涉及迁移)减值, 相比健康对照组和免疫活性的慢性乙型肝炎患者”
HBV携带者尽早治疗可能更有利作者:佚名 文章来源:医脉通 点击数:84 更新时间:2012-9-14
文献标题:Preserved T-cell function in children and young adults with immune-tolerant chronic hepatitis B.
文献来源:Gastroenterology 2012 Sep;143(3):637-45
来自伦敦的临床合作者和新加坡临床科学研究所(中心)的科学家们第一次发现患有慢性乙型肝炎病毒感染(HBV携带者) 的小孩和年轻患者确实有保护性的免疫反应。跟以前的观点相比,此次研究表明他们更应该及早接受治疗。 这个发现可能导致当前慢性乙型肝炎病毒治疗方式的转变。
国际肝协会最新指南建议乙肝病毒携带者在未出现明显的肝病活动迹象之前,不需要接受治疗。这个建议是基于两个假设。第一,年轻患者对病毒有免疫耐受,对抗病毒治疗无应答。这意味着他们的身体里没有保护性的免疫应答来帮助他们清除病毒,因此,他们不会冒着肝损伤或炎症的危险区接受治疗。第二,对于乙肝病毒携带者来说除非出现明显的肝病活动,不然乙肝病毒感染在很大程度上是无害的。
然而,Bertoletti教授和他的团队研究却表明,年轻的病人并非像他们所拥有的HBV特定T细胞能够产生不同的抗病毒因子来帮助身体对抗乙肝病毒,一样具有免疫耐受。他们的研究还说明,如果病人推迟治疗的时间越长,那么当他们接受抗病毒治疗时,他们的免疫系统产生抗病毒免疫应答的效果就会越差,且机体清除病毒的能力也会越差。
科学家们证明,乙肝病毒长时间滞留在人体里是有害,这是由于病毒将反复激活T细胞这将导致T细胞处于精疲力竭的状态,即免疫系统功能障碍。因此,与老年患者相比,年轻患者产生抗乙肝病毒的免疫应答更强。
Bertoletti教授说,“感染乙型肝炎病毒的年轻患者是最危险,但当前指南意味着他们最不可能被治疗。而我们的研究结果表明,年轻患者拥有很强的免疫系统,抗病毒治疗的免疫应答也更好,也更有可能清除病毒,所以,及早接受治疗对他们反而更好。”
研究中心的执行董事Judith教授说:“这个发现可能改变新加坡甚至全世界乙肝患者的治疗方式。”
文章编译自:Earlier Treatment for Young Patients With Chronic Hepatitis B More Effective in Clearing Virus ScienceDaily ;2012;Sep;6
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.