APASL2009王福生教授访谈

Hepatology Digest: We’re here with Professor Fu-Sheng Wang of Beijing at APASL 2009.  Thank you professor, it’s a pleasure to have you join us.  First of all, how about the conference so far, what do you feel has been a hot topic and what are some of the highlights for you especially?

国际肝病：我现在在APASL2009年会采访北京来的王福生教授。非常高兴您接受我们的采访。首先，您认为目前会议进行得怎样？另外，您认为这次会议的热点和亮点是什么？

Prof. Wang: I think this 19th APASL conference, is so far so good.  Firstly, it is very well organized although there are some things that need to be improved.  In my opinion, the hot fields are the virologic studies, and the immunologic study as well as the diagnosis and treatment for viral hepatitis and liver cancers.  There have been many advances in this field..

王福生教授：到目前为止，我认为第19界APASL年会很成功。首先，尽管有些方面还有待改善，但大会的组织工作非常出色。我认为热点领域是病毒学研究、免疫学研究、以及病毒性肝炎和肝癌的诊断与治疗。这些领域有很多进展。

Hepatology Digest: Next year APASL will be held in Beijing.  So what are you looking forward to as far as 2010 APASL and what are some things you hope to see in 2010 APASL?

国际肝病：明年APASL年会要在北京举行，您对2010年APASL年会有什么展望？您认为明年的年会会带来什么惊喜？

Prof. Wang: This is a very good question and I’m very interested.  Next year the APASL conference will be held in Beijing.  I have talked with Professor Jia (Ji-Dong Jia) and also we need to do a lot of things, not only including the organization of the conference but also we need to think about inviting prestigious medical speakers for this conference, not only from the United States but also from Europe or from the Asia-Pacific region. In China, in my opinion, we need to invite some of the hepatologists in China to give talks in this conference.  I’m looking forward to the coming of the APASL meeting to be held in Beijing, I’m confident that the APASL meeting will be successful.

王福生教授：这是个非常好的问题，我对这个问题也很感兴趣。明年APASL年会将在北京举行，我曾和贾继东教授讨论过，我们都认为还有很多事情要做。不只是安排大会的组织工作，还要考虑邀请享誉盛名的医学专家来作为大会发言人，这些专家不仅来自美国，还有来自欧洲及亚太地区的。我认为，我们还要邀请中国的肝病专家在这次大会上讲话。我期待着在北京举办的APASL年会。我相信这次APASL年会将会成功举办。

Hepatology Digest: I’m sure as well.  It’s very exciting; it’s the first time it will be held in Beijing and in mainland china so it’s very exciting.

国际肝病：我也相信这一点。这是APASL年会第一次在中国大陆北京举办，非常令人激动。

Prof. Wang: Also we are looking forward to more and more Chinese hepatologists attending or participating in this important conference.

王福生教授：我们也希望有更多的中国肝病学者能参加这次重要的会议。

Hepatology Digest: I’m sure it’s much easier because of the travel issues and such and it will really make the local Chinese attendance higher than perhaps when it was held in other locations such as Tokyo or Seoul.

国际肝病：当然，我相信这会容易多了，因为没有交通费用等问题，与历届在其他地区——例如东京、首尔等举办的会议相比，这次中国本地的与会者可能要多一些。

Prof. Wang: Yes. I think probably that the estimated participants will be over four thousand.

王福生教授：是的，我估计参加人数可能会超过4千人。

Hepatology Digest: I’m sure it will be a very successful conference.  So moving on to some things that are more technical in nature, when we talk about innate immunity and adaptive immunity, which one might play a more important role in the elimination of the Hepatitis B virus?

国际肝病：我确信这将是非常成功的大会。现在，我们回到专业性的问题上，当我们谈到先天性免疫和获得性免疫时，您认为哪种免疫在清除HBV DNA过程中起更重要的作用？

Prof. Wang: Well I think this is a very good question, also a very tough question to answer.  Generally speaking, in the human body the innate immunity and the adaptive immunity both of them play an equally important role in control of the viral infection as well as the clearance of the virus in vivo.  Generally speaking, the innate immunity just plays a very quick rapid role in control of viral replication. When the virus enters the human body maybe within 20 minutes this innate immune system plays a very important role in controlling the virus.  Combatants of innate immunity include NK cells (natural killer), macrophages, dendritic cells as well as other neutrophils.  For example the dendritic cells, one of them is the   plasmacytoid dendritic cells.  They just release a huge amount of interferon-alpha when the virus enters the human body so in this way innate immunity plays a very crucial role in control of viral replication.  But on the other hand, we can see the adaptive immunity also plays a very important role in controlling the virus.  For example, the innate immunity cannot completely clarify the virus in vivo, when the adaptive immunity works at the same time or we can say simultaneously, the innate immunity can induce or activate the adaptive immunity and then the viral specific CD8 (cytotoxic) T-cells can be produced and these cells are very unique and very special to control the viral infection also they clear out the virus in hepatocytes or within cells.  Both of them are very important.

王福生教授：我认为这个问题很好，但这个问题也比较难回答。一般来说，人体内的先天性免疫和获得性免疫在控制病毒感染和体内清除病毒方面有同等重要的作用。一般来说，先天性免疫在控制病毒复制中起超快速反应作用。可能，先天性免疫系统可能在病毒入侵体内的20分钟内，在对病的读的控制方面起重要的作用。先天性免疫的效应细胞包括NK细胞（自然杀伤细胞）、巨噬细胞、树突状细胞和中性粒细胞等。例如，树突状细胞中有一种浆细胞样树突状细胞。当病毒入侵人体时，它能释放大量的干扰素-α，通过这种方式，先天性免疫在控制病毒复制方面发挥了重要作用。另一方面，我们看到获得性免疫在控制病毒方面也起重要作用。例如，体外实验显示，先天性免疫不能彻底清除病毒，在获得性免疫发挥效应的同时，或者说，在先天性免疫诱导或激活获得性免疫发挥效应的同时，可以产生特异性针对病毒的CD8T细胞（细胞毒T细胞）。这些T细胞在控制病毒感染和清除肝细胞内病毒方面发挥独特的作用。所以这两种免疫都很重要。

Hepatology Digest: How is the research in these two fields contributing to the development clinically and influencing which agents are developed?  How is that influencing development?

国际肝病：有关这些领域的研究进展对已经生产出的药物有什么临床意义？这种影响有什么进展？

Prof. Wang: So far more attention has been focused on adaptive immunity.  In particular, many studies have focused on the HBV specific CD8 t-cells because these kinds of cells are very important.  They play a very important role in clarifying the in vivo virus by two mechanisms.  One mechanism is non-cytotoxic effect.  We just call this ‘HBV specific’.  CD8 t-cells can release the endogenous interferon-alpha, TGF-beta (TGF-β) and then TNF-alpha and interferon-gamma (IFN-γ).  The endogenous interferon-gamma can clarify the infected virus within hepatocytes but on the other hand the HBV specific CD8 t-cells can damage the hepatocytes.  The t-cells have been infected by the HBV so this can lead to damage of the hepatocytes and then induce the elevation of ALT levels in serum.

王福生教授：目前我们对获得性免疫给予了更多的关注。特别是，很多研究已经把焦点集中在HBV特异性CD8T细胞，因为这类细胞很重要。它通过两种机制发挥清除体内病毒的重要作用。一种机制是非细胞毒效应。我们称为“HBV 特异性”。CD8T细胞能释放内生的干扰素-α、转化生长因子-β、肿瘤坏死因子-α、干扰素-γ。大量的干扰素-γ能清除被感染肝细胞内的病毒；但另一方面，乙肝特异性CD8T细胞也会导致肝细胞损伤。T细胞能被HBV 感染并导致肝细胞损伤，随后引起血清ALT升高。

Hepatology Digest: Some new immune agents have been added to the therapy regime of some viral diseases and treatment of tumors, such as peptide vaccines, etc..  What are their applications in treatment of chronic hepatitis B?

国际肝病：一些新的免疫药物已经被应用于部分抗病毒疗法和肿瘤的治疗中，例如，肽类疫苗等。在慢乙肝的治疗方面，它们的应用情况如何？

Prof. Wang: Well so far there are many clinical trials.  We just call it immune therapy or regulatory immune therapy for patients with chronic hepatitis B.  This includes HBV antigen positive dendritic cells or we just call it HBV DNA vaccine or we call it the cytokine-induced killer cells, CIK cells.  These kinds of immunocells right now have been used in clinical trials for immune therapy in patients with chronic Hepatitis B.  So far all the clinical trials just in on going studies, the efficacy of these kinds of immune therapies needs to be carefully evaluated in the future.

王福生教授：目前已经进行了很多临床试验。我们称其为针对慢乙肝患者的免疫疗法或者调控免疫疗法。包括：HBV 抗原性阳性的树突状细胞，或我们称为“HBV DNA疫苗”，以及我们称为“细胞因子诱导的杀伤细胞（CIK细胞）”。目前这些免疫细胞已经被应用到慢乙肝患者免疫治疗的临床试验中。目前所有的临床试验研究都在进行中，再将来，这种免疫疗法的治疗效果都需要被仔细评估。

Hepatology Digest:  You mentioned ongoing clinical trials, how about you personally, what are some of the latest studies that you are working on?

国际肝病：您提到了正在进行的临床试验，就您个人进行的工作来讲，最新的研究是什么？

Prof. Wang: I’m very interested in these fields.  So far I am involved in two projects that are underway by my team in my clinic department for treatment of the patient with chronic hepatitis B.  One is the HBV surface core antigen-pulsed dendritic cells.  We have finished the pre-clinical studies and hopefully we just got formal approval for this kind of therapy in clinic just earlier this year.  Right now, another project we just called CIK therapy we also call autologous cytokine induced killer cell therapy for patient with chronic hepatitis B.  And then we have finished the initial clinical trials.  Our data has been published in the Clinical Immunology just in recent issues and also other paper was published in Liver International.  I think in the February issue of Liver International.

王福生教授：我对这些领域都很感兴趣。目前在我的慢乙肝临床治疗部门，主要在进行两个项目的研究。一个是关于对HBsAg和HBcAg敏感的树突状细胞。我们已经完成了相关的前期临床研究，有望在今年早些时候取得了对这种疗法临床应用的正式批准。现在，另一个研究项目是被我们称之为“CIK疗法”或者“自体源性细胞因子诱导杀伤细胞疗法”在慢乙肝患者中的应用。我们已经完成了初期临床试验。数据已经发表在近期的《临床免疫学》杂志上，其他的文章将会发表在大概2月出版的《国际肝脏》杂志上。

Hepatology Digest: Studies have shown that the expression of HBsAg and HBeAg contribute to the immune tolerance of the Hepatitis B virus.  So can you talk about the mechanisms of this?

国际肝病：研究表明，HBsAg和HBeAg的表达有助于免疫耐受的发生。那么，您能否谈下它的机制？

Prof. Wang: This is also a good question.  Before that I would like to give some comments from our studies of CIK clinical trials.  In our studies clinical trials for CIK therapy for a patient with chronic hepatitis B we did find that this kind of therapy we called autologous   CIK therapy could control their HBV replication in vivo.  50% of the patients are definite responders.  This means there is a full viral suppression in the responders.  Anyway in the other remaining 50% of the participants we just call partial or non-responders because the viral suppression is not fully occurred or exist.  Well for your question regarding the HBV antigens’ contribution to the immune tolerance in vivo, so far much attention in all over the board has been paid in this field.  As we know the higher viral load also contributes or leads to the immune tolerance in vivo.  But so far, according to the advances in research we found that antigens also play a very important role.  In this way we just divided this into two aspects.  One aspect we call, called of them the virologic factors that lead to immune tolerance in vivo.  One aspect is the viral load.  This has been discussed before and demonstrated in previous studies but for e-antigen and in the surface antigen the hepatologist considers that they are very important in inducing the immune tolerance because this kind of antigen can induce the impairment of dendritic cells and also can induce the generation of regulatory t-cells.  Regulatory t-cells are a kind of suppressive immunocyte in the human body.  The regulatory t-cells can inhibit the HBV specific CD8 t-cell function.  Also can suppress the immune response against HBV so in this way we can see the surface antigen and the e-antigen both of them efficiently contributed to the occurrence of immunotolerance status in a patient with chronic hepatitis B.

王福生教授：这也是个很好的问题。回答这个问题之前，我要谈下我们关于CIK的临床试验研究。在对乙肝患者进行CIK疗法的临床试验中，我们发现，这种呗我们称为“自体源性CIK疗法”能控制体内病毒的复制。50%的患者有明确的应答。这意味着在这些应答者中有完全的病毒抑制。然而，我们称其他50%患者为“部分应答或无应答”，因为他们的病毒抑制不完全或还存在。现在，针对你的问题，体内HBV抗原的存在有助于免疫耐受的发生，目前已经引起了世界范围内该领域很多学者的重视。我们知道，体内高病毒载量有助于或导致免疫耐受的发生。根据目前的研究进展，我们发现，抗原在免疫耐受过程中也起重要作用。由此，我们能将机制分为两部分。一部分我们称之为体内导致免疫耐受发生的病毒因素。另一部分是病毒载量因素。HBeAg在诱导免疫耐受方面的作用已经被讨论过并在以前的研究中证明过，现在肝病学家认为HBsAg在诱导免疫耐受方面也有重要作用，因为这类抗原能诱导树突状细胞的损伤，并能诱导产生调节性T细胞。调节性T细胞是人体内一类抑制性免疫细胞。调节性T细胞能抑制HBV特异性CD8T细胞的功能，也能抑制针对HBV DNA的免疫反应，由此我们可以看出，HBsAg和HBeAg都能有效的导致慢乙肝患者免疫耐受状态的出现。

Hepatology Digest: Once again, Professor Wang, thank you again for joining us today.  It was great to hear about your latest research and we will hopefully see you in Beijing in 2010.  Thank you very much.

国际肝病：Wang教授，再次感谢您接受我们的采访。非常高兴听到您的最新研究，希望在2010年北京的APASL年会上再次见面。非常感谢。

Professor Wang: Thank you very much, it’s my great pleasure to be here. 

王福生教授：非常感谢，非常荣幸来到这里。