| [APASL2012]慢性乙型肝炎（CHB）肝炎突发的病毒学和免疫学机制——Prof.Antonio Bertoletti专访 -----
来源： 作者：Antonio.Bertoletti 发布时间：2012-2-21 14:34:02 阅读：224
Again we say there are activated T cells that are recruited in the liver. They are also able to release other cytokines， and it does now seem more important that the same macrophages and granulocytes that are recruited by the same chemokines， that are recruiting these activated cells， are important for liver damage.
IHEP: In your presentation you were talking about the effect of liver damage on immune response and how T cells affect liver damage. A lot of us assume that T cell response is connected to a more damaged liver， but you said something a little different than this.
Dr Bertoletti: Yes there is definitely this general idea that the quantity of the T cells is absolutely proportionally correlated with liver damage. In reality things are much more complex. We have data both in animal models and in patients that are showing that the T cells are important， but they are probably important as they show the start of inflammatory events in the liver. Therefore， what does this mean? Probably if we you have a good T cell response， you have some liver damage， but this is then going to completely clear the virus， and you don’t have a persistent chronicity. And that’s what is happening in acute hepatitis B - damage， control of the virus， and no chronicity anymore. In patients with chronic hepatitis the data shows that you have some T cells that are not functionally able to fully control the virus， and therefore they start to recruit other cells - other inflammatory cells， macrophages， granulocytes - that are actually the real cause of the liver damage. Therefore we say the inflammatory events that can be triggered by inefficient T cell response are the greater cause of liver damage.
IHEP: The inefficient T cell response triggers inflammatory events by recruiting the other non-HBV specific T cells. Why does that cause inflammation?
Dr Bertoletti: Again we say there are activated T cells that are recruited in the liver. They are also able to release other cytokines， and it does now seem more important that the same macrophages and granulocytes that are recruited by the same chemokines， that are recruiting these activated cells， are important for liver damage. Granulocytes can actually release many enzymes that can directly. And they perpetrate this chonicity of inflammatory events that is present in chronic hepatitis B.
IHEP: What can you tell us about the slides shown today where chimpanzees were given very low viral loads?
Dr Bertoletti: Yes this was very interesting work that was done in the Scripps Clinic. And again that’s something that is going a little bit against the classical dogma. Generally speaking， we were thinking that large quantities of virus might actually cause chronicity. In reality what this research has shown is that it’s not only that the quantity of the virus is important for chronicity or control， but he showed that a very low quantity of virus， and probably with the virus there is a replication lowering that is not detected by the new system. And therefore， we say it’s then reaching a threshold of quantity that cannot be controlled anymore. And in that data， he really showed that apparently only one in ten viruses injected in a chimpanzee were able to cause chonicity. I would say this is interesting， and there is also other data in other animal models， where they are showing that: when there are very few viruses that are replication lowering， these viruses are not detected by the immune system. They are sort of sneaking out from the recognition of immunity. And therefore they are causing chronicity. It is not always that the large dose is causing chronicity. And yes there are many aspects that we still don’t understand， and they are very interesting and are against our normal dogma.
IHEP: So perhaps it’s not just the absolute number of the virus that alerts the immune system， but the amount that the virus is replicating.
Dr Bertoletti: Yes， correct. It is the speed of the replication. It is the speed of the replication at that point is triggering
IHEP: You talked a lot about liver damage and how it affects our immune response. So if we have liver damage， do you have an immune deficiency?
Dr Bertoletti: I show this data because I think it is interesting to see how release of enzymes from the damaged hepatocytes can not only suppress the immune system， and particularly arginase. Arginase seems to inhibit the T cell response， not only specific for the virus， but the general immune response. Again this is very old data， like 20 years ago they were already showing that there was something in the serum of the patients that can suppress these T cells. Then your question is: If we can see that arginase， the enzymes that are released by the hepatocytes can actually suppress all of the immune system. Does it mean that we may have other viral infections? I think， again， this is something that apparently is not (done/looked at) so frequently in clinics， even though there is some data suggesting that there may be some reactivation， for example， simplex virus infection in some patients with acute hepatitis. But the point is that probably this suppression is somehow a suppression that is only reducing the general high quantity of gamma-interferon of inflammatory cytokines. These cells are not completely paralyzed. They are still able to control other viruses. Therefore you don’t have a very severe immune deficiency. This mechanism is probably just a mechanism that the organ is using to block excessive liver damage.
IHEP: Does this liver damage restrict one’s ability to respond to the hepatitis B virus?
Dr Bertoletti: Probably yes it is restricted but it’s probably here also a question of kinetics. You have damage when you already have good T cells that are already somehow clearing a large part of the virus. And therefore I honestly don’t think this could happen， and it could actually be a factor that is important for the chonicity. I see it more as a fact of， let’s say， avoiding At the end of the day we can see that the FMHEP hepatitis can help hepatitis B， but it is rare， it’s about 1 or 2%. Even though we know that all the hepatocytes are always infected， and we have a good T cell response. So somehow you would think you would have more cases of FMHEP because all the hepatocytes are infected and you have good T cells. This is not happening. Probably it’s not happening because you have this sort of mechanism that are somehow saying to the immune response “ok that’s it， you have already started to clear the virus， but now stop， take a little bit more time because otherwise you are going to destroy the liver.”
IHEP: The last doctor talked about how we should be using immunological control to start treating hepatitis B and he said that you were doing some work on this.
Dr Bertoletti: Yes we have tried to develop a potential way to restore immune response. At the moment what we have done is be able to select antigen specific T cells from the acute patients; we clone the T cell receptor; the T cell receptor is the element that is giving the specificity to the T cells. And we able to take this T cell receptor and put it in the same T cells of chronic patients or of normal individuals. So in a way we are able to reconstitute an antigen specific T cell response. We have done some work in vivo and in the animal models， and we are showing that the gene therapy， because in reality it is a gene therapy. We are taking the gene of a T cell receptor and putting it in the T cells， and this is able to restore an antigen specific disorder. This is working in mice and it’s working in vitro. We have not yet done work in humans; however， we now have started to treat patients， not with chronic hepatitis， but with hepatocellular carcinoma that is expressing HBV antigens， and we introduce T cells that are able to recognize HBV antigens in these patients， particularly in patients with metastasis because we have already selected patients with hepatocellular carcinoma metastasis that are able to express HBV antigens and we will try to use this adoptive transfer of T cells specific for this antigen to clear this metastasis. I think at the moment this therapy is a little bit too experimental to be tried in patients.
IHEP: So you would only use it in the more dire case?
Dr Bertoletti: At the moment， yes because we are still afraid that adoptively transferring large quantities antigen specific cells in chronic patients might actually cause some liver damage.
IHEP: What do you think will be the next step that we need to take before we can start using it in chronic HBV?
Dr Bertoletti: I think first we need to try this treatment in patients’ hepatocellular carcinoma and really see whether we are able to control the liver damage that could occur. I am actually confident that this is not going to happen. For example， I would like to remind you again about some of the data that was presented Fu xing wen. He showed that bone marrow transplantation is actually able to control some viral infections in chronic patients. The bone marrow transplantation is a similar thing. You take bone marrow with antigen specific T cells and put it in a patient that has a chronic infection. There were cases where yes they have acute hepatitis， so there was liver damage， but then the patient was able to control. I think we really need to understand better the ratio between antigen specific T cells and liver damages and see when it could be safe to introduce a certain number of T cells in patients with a certain level of viral infection. | 
发表于 2012-2-29 18:24
