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[CIHS访谈]乙型肝炎免疫治疗进展

来源:国际肝病网 日期:2017-05-31 09:36;作者:gjk    

  编者按:Antonio Bertoletti博士,新加坡杜克-国立大学医学研究生院教授。“第三届中国国际肝病论坛”召开期间,Bertoletti教授介绍了“新的免疫治疗的最新进展-激活天然免疫或获得性免疫”,并于会后就相关话题接受了《国际肝病》的专访。
[CIHS访谈]乙型肝炎免疫治疗进展
  《国际肝病》:慢性HBV感染如此难以治愈的主要原因是什么?
 
  Antonio Bertoletti教授:乙型肝炎病毒很难被清除,母婴传播的HBV可导致机体免疫系统发生变化,适应性免疫、T细胞、抗体应答等都对病毒不起作用,或者功能受损。尽管可用很好的药物来阻断病毒复制达到免疫控制,但慢性患者的免疫系统仍会发生功能损伤。
 
  Prof. Bertoletti: Thank you for the question. Hepatitis B is very difficult to be cured because the immune system against the hepatitis has been really altered by the fact that the infection has been acquired from birth and therefore the adaptive immunity, the T cells, and the antibody response, has been completely deleted or is functionally impaired in these patients. Even though you have good drugs that can block viral replication the immune system is necessary to have complete control but the immune system is very functionally impaired in patients with chronic hepatitis.
 
  《国际肝病》:天然免疫和活动性免疫在慢性HCV感染的自然史中发挥什么样的作用?
 
  Antonio Bertoletti教授:天然免疫是免疫系统的一部分,对最初的感染控制至关重要。如果没有好的天然免疫,病毒感染很容易扩散。病毒的控制同时需要天然免疫和后天适应性免疫,尤其适应性免疫对长期病毒控制很重要。二者缺一不可,否则均会引起病毒大量复制,形成慢性感染。慢性感染实际上是免疫系统缺陷所致病毒失控。
 
  Prof. Bertoletti: Ok so the innate immunity is a branch of the immune system that is important for the initial control of infection. Clearly if you do not have a good innate immunity the virus can spread.We need the innate and adaptive immunity which are important for the viral control. Innate immunity is important for the initial control of viral replication. Adaptive immunity is important for the long term control. If you do not have one of the two branch of the immune system then the virus can replicate and can infect many hepatocytes and therefore I would say it is able to establish a chronic infection. Chronic infections have actually a defect of both branches of the immune system and therefore they do not control the virus.
 
  《国际肝病》:有什么血清学指标可以反映慢性HBV感染者的机体免疫功能吗?
 
  Antonio Bertoletti教授:目前慢性乙型肝炎没有确切的血清学免疫指标,但有显示病毒复制水平的指标。如果病毒被免疫系统抑制,可在血清中检测到抗体和特异性T细胞抗原。通常慢性乙型肝炎患者的HBV特异性T细胞较弱,抗体水平也很低。
 
  Prof. Bertoletti: No there are no real markers in patients with chronic hepatitis. We have markers if a patient is able to control the virus. If the virus is controlled by the immune system then you can detect antibodies and you can detect antigen specific t cells. Usually patients with chronic HBV infection have a very low frequency of HBV specific t cells and the level of antibodies is very small.
 
  《国际肝病》:有可以提高先天或获得性免疫功能的乙型肝炎治疗新药处于或已经完成临床试验评估吗?
 
  Antonio Bertoletti教授:目前有很多药物在研发中,但已经进入临床试验的不多。其中有一些药物可活化肝内天然免疫功能,例如TLR-7激动剂,已经通过动物实验,但是在人体中只用了很低剂量,虽没有引起毒副作用,但也没明显效果。现在针对激活适应性免疫功能的药物主要是疫苗,正在进行临床检测,但也未有很好的疗效。目前一项新的治疗方法可设计特异性T细胞抗原作用于信使RNA而抑制病毒复制。总而言之,免疫疗法的药物基本还处于动物实验阶段。
 
  Prof. Bertoletti: There are many drugs which are in development. There are not so many drugs which have already been tested in clinical trials. There are been some drugs that are designed to activate the innate immunity within the liver the intrahepatic innate immunity, for example one is the tlr 7 agonist that is activating the main cells that are resident in the liver. This has been tested in animal models but tested in humans with only a very low dose. This does not cause any toxicity but did not show any efficacy. For drugs that instead have a design to boost their adaptive immunity there are vaccine therapies, which have at the moment being tested. So far again there are none with fantastic results and then there are new potential for new treatments that can engineer antigen specific t cells that can inhibit the quantity of virus with messenger RNA but as we say, at the moment the data that we have for drugs that are immunotherapy mainly are being tested in animal models.
 
  《国际肝病》:随着将来有更加强效的抗病毒药物和免疫疗法可用,以及婴儿免疫计划在全球得到普及,我们可以期待有机会在全球范围内消灭HBV吗?
 
  Antonio Bertoletti教授:实话说,根除HBV似乎不太可能。HBV是一种和人类物种同时起源甚至更早的一种病毒,我不认为它可以被完全清除,但可以达到某种程度的抑制。临床上部分患者携带病毒但不会发展成慢性疾病造成肝脏损伤。我不认为HBV可以被彻底根除,它不同于HCV,HBV是一种DNA病毒,一般来说人体内所有的DNA病毒都不能被根除。有些病毒会激活机体天然免疫,可能并不完全是致病的,所以我们并不都需要将其灭绝。
 
  Prof. Bertoletti: To be honest, eradication seems too ambitious. I do not honestly think a virus like hepatitis b which has probably been with the human species from the birth of our species and even before probably, can be completely eradicated. We can probably reach some sort of control. We see patients who still harbor viruses but perhaps they are not going to develop chronic sequelae or pathology of the liver. I do not think at the end of the day that we will be able to completely eradicated. It is a completely different virus than hepatitis C, it is a DNA virus and in general all DNA viruses are not eliminated in our body. Perhaps having some virus might not be completely bad because it can actually boost your innate immunity so I do not think we will reach eradication.

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