Norman Swan: Hello and welcome to this week's Health Report with me, Norman Swan. The immune system is fantastic when it works well and terrible when it doesn't. In this episode of the Health Report we canvass new frontiers of knowledge in the immune system, from infancy through to adulthood and problems like allergy and cancer.
The program is based on a panel which we recorded at the World Science Festival back in March. The panel included cancer biologist Nigel McMillan from the Menzies Health Institute in Queensland, Katie Allen who was at the time a paediatric allergist from the Murdoch Children's Research Institute in Melbourne, who has since become a member of parliament for the seat of Higgins in Victoria; and Mark Smyth, who is a senior scientist and immunology coordinator at QIMR Berghofer Research Institute. And he starts with a primer in immunology.
So get your notepads out and we will question you later—multi-choice questions as we go through. So Mark, take us through an initial primer on the immune system.
Mark Smyth: Okay, well most of you are probably familiar with the immune system from having a bit of understanding about your blood, particularly, and that contains a group of cells. You know you've got red cells, which colours the blood, and you have white cells. So the immune cells basically sit in that white cell fraction.
Perhaps what you don't know so much about is that the immune cells actually originally develop in your bones, in a place called the bone marrow, so they have a very specific niche there that they develop in. And they develop in all kinds of different what we call lineages or types of cells. They do their initial developing there and then they get seeded out into the periphery, into the different organs.
The immune system's interesting, a lot of people don't realise that the biggest immune organs that we have are our skin, and also our gastrointestinal tracts. I think there's been some survey done about how much immune system we've got in the gastrointestinal tract—it's an enormous amount. Many, many tennis courts' worth of surface area of the immune system.
Norman Swan: People think of the gastrointestinal tract as inside your body; it's actually outside your body. It's an external surface, it just happens to be a tube inside your body.
Mark Smyth: That's exactly right. So those particular immune organs of course are exposed to all the potential antigens, food antigens and also…
Norman Swan: I guess we should define our terms here. An antigen is something that provokes an immune response.
Mark Smyth: That's right. An antigen is something that is seen basically as foreign by the immune system. So when we think about the immune system fighting things like viruses and bacteria, these are organisms that are foreign to ourselves.
So in the development of the immune system there's a selection process, particularly cells of what are called the adaptive immune system are selected to particularly see what is foreign. They become tolerant to what is self, or normal. So that's a very important process. That sort of sets your threshold for life in terms of what you can see.
Norman Swan: So it doesn't attack your self, it's designed to attack foreign…
Mark Smyth: To attack foreign, that's right. When we're talking about immune cells, though, there's two basic types, really. To break it down very simply, there's a group of cells which act very early in an immune response, and they're very primitive cells. Virtually all organisms have those cells, going right down to things like snails. And they have the same types of cells that we do.
And we can talk a bit more about those types of cells. I work on one of those groups of cells called natural killer cells. Nigel will talk a little bit about macrophages and myeloid cells. So these are the early responding cells, and they basically fall into two categories. They're killer cells or they eat things. And their job is to really deal with something very early on. Now the eating is all about basically transferring information to the next part of the immune system which is the adaptive.
So they eat, they take in the information and then they present it to these cells that have got great specificity. The killer cells obviously just kill and try to eliminate and remove the virus or the bacteria or the fungus or whatever it is.
After that innate phase, that innate phase is very critical for your protection in the first few days of when you get infected with something, but then you move to what's called the adaptive system, and that's where the cells that I was talking about like T-cells are educated, and D-cells. So T-cells essentially see little pieces of proteins that are foreign and presented on the surface of other immune cells, and those T-cells can do all sorts of different things, and we'll talk about that. And they form what we call memory.
The other type of cells that we have are B-cells, and they make things called antibodies, which are essentially structures that recognise foreign things, combine them, and then other cells attach to that and destroy those. And those antibodies also have specificity and we also have memory. So when we get vaccinated with, you know, the initial vaccines we have in our life, it's basically the B-cells making antibodies that are giving us lifelong protection against those types of challenges.
Katie Allen: So Mark it's a bit like an army, isn't it, so you have the rapid response part of the army which is the ones that come out with bows and arrows, and then you've got the next adaptive ones which come out with the more sophisticated machinery.
Mark Smyth: That's right.
Katie Allen: And the difference between the cells are what's on the outside of them, because those cells have little, like t-shirts, telling which army or which types of military information they can use and not use, and which ones they can attack and which they can't attack. It's like a code, isn't it.
Mark Smyth: That's right, yes.
Norman Swan: So, Katie, when it comes to growing up with your immune system, your immune system gets trained, doesn't it?
Katie Allen: Yeah, it gets trained, particularly in that first year of life, it's a very important time. And as Mark said before, the first exposures that you get are either through the skin, through the airway or through the gut. And so your system has to be ready, and it starts off with the first line of attack, which is that innate immune system, and then there's this adaption, the adaptive immune system which is the more sophisticated part of the immune system.
It's very complex, and in fact immunologists, and I'm not one of those, will argue about the specifics of one part of the immune system, but it's very, very hard to understand the complexity of all the immune systems. And I often think we should have a video game around it, because if you could have young people with smart minds sitting down trying…they can all recognise…when you watch my kids play on video games, they know the interactions that you can and can't have, and the immune system is like that. It knows the codes and the rules, and we're trying to work out the jigsaw puzzle around that.
Norman Swan: People say that allergy is the result of poor immune training. What do we know about that?
Katie Allen: So allergies in particular in one part of the adaptive immune system, we think the innate immune system has an important role to play in setting up the problem, but the adaptive immune system that goes wrong is what we call the IGE mediated antibody system. And the IGE system…
Norman Swan: This is the chemicals that float around in your blood, rather than are attached to white cells and…
Katie Allen: So what happens is there are cells that have IGEs attached to the outside of them and then when…
Norman Swan: Immunoglobulin…
Katie Allen: Immunoglobulin, yeah, and then what happens is—and you can see, it's a little bit like having a grenade. And what happens is comes along is something like a food attaches to parts of the spikes and causes that cell to detonate, and out of those cells come chemicals, such as histamine and many of you will have heard of antihistamines. So those histamines cause reactions in your body that make you itch or swell or have anaphylaxis.
Norman Swan: So is it true that the part of the immune system that goes rogue with allergies is the one that was designed to fight parasites in ancient times?
Katie Allen: That's absolutely correct. And that's why we think it's something to do with the modern lifestyle.
Norman Swan: And, Nigel, what goes wrong when you get autoimmune disease? What do we know about the lack of ability to recognise self? I realise I might be taking you out of your comfort zone here.
Nigel McMillan: In an autoimmunity the problem is our cells have to learn what to look for, and it's really important that this occurs early in life. But our immune system will sometimes make a mistake. And it will start going a bit rogue. So we have cells that have very specific identities. All our cells are known to ourselves, that's why you can't take a blood transfusion from one type of person to another if it's not matched immunologically, because they will reject it.
We know what our self is. But sometimes our immune system makes a mistake, and it will start recognising, say, in the case of MS, part of our sheathing on our nerve cells, it starts making antibodies and it starts making T-cells, cells that will break them up—against our self. And of course this is an enormous problem because we have memory there and it keeps on going. And treating those is basically a matter of turning our immune system down with drugs like steroids and the like, and that has its own problems as well.
Norman Swan: So, first hunter-gatherers and then we evolved into homo sapiens, infection was our biggest problem. Talk us through how we fight infection.
Nigel McMillan: So we've all probably suffered from the influenza virus or one of the many viruses that cause the common cold—rhinoviruses, for example. So the first thing that happens is this virus gets in our nasal passages and gets into our lungs, and the first thing it will actually encounter will be one of these sort of guardian cells. Think of this as a castle siege. These are the lookouts outside the castle, looking for invaders. These macrophages. Macrophages are very good, because it recognises molecules on those bacteria and it eats them, and takes them and eliminates them.
Now macrophages, we have a whole set of macrophages in our lungs; we call them alveolar macrophages. They're really good at bacteria. They're not so good at getting viruses so much. But we then have anther line of defence, so think of the castle, we have lookouts outside the castle. If they start sieging the castle walls our castle is lined with people who signal inside the castle that we're under attack from a virus. And it releases pigeons to go and send help to other castles to bring help, and we call these cytokines. Now there's one particular amazing one. The name of it is interferon; it doesn't particularly matter, but interferon is an amazing signalling molecule that turns 1,000 new genes on in your cell, and they are to fight that virus. It also goes off and signals other cells next door, to say look out, viruses are around.
If I was to inject you with interferon, you would feel like you had the flu—aching joints, temperature, sweats, chills, et cetera.
Norman Swan: Which is in fact what they used to do for hepatitis and don't do anymore, because of the awful side effects.
Nigel McMillan: Yes. So basically when you were treating patients for hepatitis you gave them flue for six months, which was fairly depressing, for sure. Luckily we have really good new therapies for hepatitis. So this is this innate immune system Mark was talking about. It doesn't improve over time, it just tries to slow the virus down. But the virus eventually—viruses are really sneaky—they've got so many ways of subverting our immune system. Every virus that's alive today is here because it's worked out how to get around the immune system. So I tell my students, your job's easy. It's all done. You just have to find out how it works.
Norman Swan: Now we throw the word 'inflammation' around a lot. Everybody in this audience has used the word 'inflammation'—you know, the redness on their skin, part of a rash. But it's got a very specific immune meaning. What is inflammation?
Nigel McMillan: So inflammation is the activation of these immune cells, so another set of chemical signals are released and we get activation of cells like—we call them mast cells and the like—that essentially brings a whole lot of new players to the site. And you look at where you might have a bacterial infection on your skin, it goes all red. That's because there's a whole lot of new players coming in, these macrophages, these neutrophils, and then eventually these smart cells. I call these like the secret police. They are the really smart cells that kill off bacteria eventually, these CD8 and CD4 cells. And that inflammation is just reflective of a really great immune system, but of course sometimes it goes wrong.
Norman Swan: And inflammation's part of allergy.
Katie Allen: Yes, yes. In fact we call it inflammation, because traditionally, as you said, people think of inflammation, they can see redness and swelling and pain. But inflammation is in theory recruitment of immune cells to try and solve a problem. And in the case of allergy, the problem is a misfiring. There's been an alarm that's been set up, then the body's just got confused about what the actual signal is.
Norman Swan: You're listening to RN's Health Report with me, Norman Swan, and a panel on the immune system recorded at the World Science Festival in Brisbane.
Transition us now to cancer. What's the cancer story in all this, because when I was at medical school we were told that the immune system didn't have anything to do with cancer whatsoever, it was just irrelevant, some mad idea.
Mark Smyth: I was exactly in the same boat. There's a very famous Australian immunologist actually, Macfarlane Burnet, who is known for what's called the clonal selection theory, which was to do with D-cells. But a lot of people don't realise he actually also proposed another theory called the cancer immune surveillance hypothesis back in 1957. And that hypothesis is basically that your immune system goes around and recognises anything that is transformed or different or not normal. And there are lymphocytes in your body, T-cells he was thinking about—T-cells were just being discovered in his institute at that time—and they'd go around and they roam around and we've got some pictures there just showing you some surveillance on the screen. Small lymphocytes surveilling tissue and looking for cells that are rogue. And essentially the process is to potentially eliminate those cells so that those cells never become a problem.
So when cells become cancerous, it always starts at a single-cell level. So if you can get rid of that cell in the first instance, the cancer will never develop. So when we think about what's evolved in terms of our understanding of cancer and the immune system is that the current theory is that there are three phases. You have what we call elimination, as I've just described, where nothing ever eventuates; your immune system acts effectively, removes those dangerous cells.
We have a phase called equilibrium, where cells start to avoid those all sorts of different controls on them—intrinsic controls but also immune system controls…
Norman Swan: So they're starting to behave like bacteria do to resist the immune system.
Mark Smyth: Cancers are genomic, what we call genomically unstable, so their chromosomes are very unsettled, they can mutate very quickly. So they start to develop resistance, if you like, to the immune system. The immune system at the same time is trying to get rid of that, and there's a selection process that goes on. Not surprisingly, sometimes that long battle—and that can actually go on, we've shown it in experimental animals, it goes on for the length of an experimental animal's life.
In humans this could be happening in people for decades, potentially. Nothing eventuates, but then you get what we call escape, where the tumour essentially develops a strategy where it can overcome the immune system, a clone of that particular tumour, and it grows out. And that's what we see in the clinic. So when someone comes to the doctor and they've got a lump or some sort of issue with one of their organs and we find a mass, that's actually a pretty late stage of events, really. The immune system has had a history with that cancer, perhaps for many years, depending on how malignant or tumorigenic that cancer is.
Katie Allen: And clinically there's been a real change in the way people are thinking about cancer in that we now have some really exciting new therapies coming online: monoclonal antibodies and immunotherapy. But people talk about in the future we'll be living with not just one but several cancers, and how we manage those, because there'll this whole sort of balance between fighting a cancer and not fighting a cancer rather than you get a cancer and then you die, sort of thing. So there's been a real switch, hasn't there, in the last ten years about a hopeful outcome but that we are trying to balance our immune system and surveillance of cancers as they're emerging.
Mark Smyth: Yes, what I was talking about is really the fundamentals of your natural immune reaction with cancer. But what we've understood is that, as I said, the cancers have these escape mechanisms. Now these escape mechanisms are also points at which we can intervene and perhaps get the immune system to deal with these escape mechanisms. And so one of the mechanisms, for example, is that the T-cells that go in there, they have molecules on their surface called check points. They're like brakes. And they're essentially molecule on there to stop T-cells from rampantly going round your body and destroying your normal tissue.
So that's there for a good reason. That's to stop you having autoimmune reaction. But the cancer kind of hijacks that process, and uses that particular check point on those T-cells and interferes with that process. What we've understood is if we put in an antibody then that actually blocks that interaction, it's like a double negative. You essentially activate—you take the brakes off and you activate those T-cells. So those T-cells that were rendered inert by the cancer, are sort of reactivated and reinvigorated. And that's where the breakthrough's come in the last few years. That understanding of how the immune system works in that regard, and applying technology to develop agents that interfere at that level. We're talking about the first approval of one of those agents was in 2011.
Norman Swan: And a Nobel prize last year…
Mark Smyth: Nobel prize last year for the inventors of—well, discoverers of the check point process really. And you know, therapies that have been rolled out in multiple cancers now—and a reality check, we're not curing everybody, but we're prolonging the life of a large number of patients in some particular cancers like melanoma or skin cancer, making a tremendous difference.
But the interesting thing about the immune system is that it's agnostic to the cancer type. Immune cells can go in and destroy all different kinds of cancers, so traditionally therapy has been applied in the sense directly against cancer cells—chemotherapy, radiotherapy, surgery, which is still the most effective type of therapy—that's all designed to get rid of the cancer intrinsically, whereas the immune therapies are designed to work on your normal immune system, the normal host, if you like, and make those cells attack, liberate those cells to attack the tumour.
Nigel McMillan: But Mark with all our chemos, radiation, et cetera, et cetera, that cured many people of cancer, but is it those that are curing it, or is it really that they're debulking the tumours and the immune system is always ultimately required for a cure of cancer?
Mark Smyth: That's a really good point. A lot of people have studied, particularly radiotherapy and some types of chemotherapy actually do work through the immune system. So experiments have been done to take out elements of the immune system and apply these types of therapies, and they largely don't work without the immune system.
Katie Allen: The other layer is actually genetics as well, isn't it, and as we move forward we'll get more personalised based on the codebook you have for the type of cells you might be producing, as well, or the response that you've got…
Mark Smyth: That's right. There's an amazing intersection at the moment occurring between the genomic—so you would all know that the human genome was basically mapped out, it was a billion dollar project around 2000, and one genome; and now we can sequence people's genomes in hours, basically for hundreds of dollars. So what Katie's talking about in terms of personalised medicine is your particular cancer is unique. Because it's mutated it actually makes foreign proteins that your body sees as foreign…
Norman Swan: But gene testing is not very useful in immunotherapies from what I gather. It doesn't necessarily predict whether you're going to respond to it.
Mark Smyth: It's starting to. So there's a thing called tumour mutational burden, which is a…
Norman Swan: How rapidly your tumour is changing.
Mark Smyth: It's a broad term but it basically assesses the level of mutation you've got in your cancer. So to use an example, people who have melanoma with UV exposure particularly, causes a lot of mutation in the skin. And those people respond very well to immunotherapy. Very strange paradox—people who smoke that have lung cancer do better on immunotherapy than non-smokers. And it's because the carcinogens in the cigarettes cause more mutation in their cancers and makes those cancers more…
Norman Swan: So paradoxically a nastier tumour is more exposed to the immune system.
Mark Smyth: That's right. More heavily mutated. And so this tumour mutational burden now is being used as a predictor, with other things, to try and predict who's going to respond to immunotherapy and who isn't.
Norman Swan: Regardless of the tumour in your body. So where do viruses fit into it, because one of the early biological studies of cancer was known viruses that cause cancer.
Nigel McMillan: We know that infectious organisms cause one third of all cancers. So the most common is helicobacter, which of course discovered…the Nobel prize in Australia for that work, but it causes stomach cancer. HPV, the human papilloma virus, pretty famous in Brisbane of the vaccine that was developed here, causes about 5% of the world's cancer burden.
And so all these cancers though are a mistake. Because all viruses want to do in their entire life is make more virus. And when an HPV virus gets into a cell it accidentally gets caught up in the genome and it makes no more virus. So it's a mistake by the virus. The consequence unfortunately is that over a long period of time with more mutations it forms cancers. So skin cancers, head and neck cancers, cervical cancer.
But of course because it's caused by a foreign organism, it makes signals that the immune system should see. Generally the immune system doesn't see those very well, and all the therapies we've tried to try and treat patients after they've got the cancer with immunotherapies to date haven't been very successful. But we know if we immunise beforehand, the virus will never cause the cancer.
Norman Swan: Katie can you just talk about some of the research you've been doing at the Murdoch and how that's illuminating both the causes of allergy in babies and children and how to prevent it?
Katie Allen: The research we've been doing is really trying to understand why something like this has happened so quickly and why it's happening in the developed world. And when we talk about viruses or cancers, they've been around since time immemorial. But food allergy, literally, in what we think has happened, is really in the last couple of decades, two or three decades. And so again, as a medical researcher, to be able to identify what has caused something that has happened so quickly and in such large numbers as a public health threat, to be able to turn that around and turn off that epidemic, is very tantalising. And we do think we've discovered some of the 'ins' into that.
Norman Swan: Such as?
Katie Allen: Well, I call it the five Ds. I gave a talk once to an elderly population, and I talked about the five Ds and I went through them, and at the end one of the old dears said to me, 'Now, with regard to the three Ds…' And I thought, you can't keep it very simple, can you?
Norman Swan: You'd forgotten about the dementia D.
Katie Allen: Exactly. So the five Ds we talk about are Diet and Dry skin, which is eczema increases your risk because your skin is dry and it probably increases the alarm of the immune system to being exposed to certain foods. The second D is Diet. And so we know that delaying the introduction of certain foods into babies' diet in the first year of life is increasing the food allergy epidemic. Don't delay introducing foods we used to think might be dangerous such as peanut butter, cow's milk, egg and wheat, and to introduce them in the first year of life after solids have commenced.
Nigel McMillan: I have a three-month-old grandchild. What should I be telling her mother to do?
Norman Swan: Shovel in everything, early…
Nigel McMillan: My own eating habit…
Katie Allen: That's right, so we say around six months and not before four months is when to introduce solids, and that's because we want the World Health Organisation to agree with the allergy community. We are actually looking at whether we should be going back to what Grandma used to do. But certainly you don't need to delay them any longer. And of course we want people to continue breastfeeding, and that's one of the big political issues, is that breast is best, and for all sorts of reasons…
Norman Swan: There's not much evidence that introducing solids earlier affects breastfeeding. It's a myth.
Katie Allen: That's right. And the issue is really around the developing countries where formula companies were aggressive, and introducing formula too early, and that water that was associated with the developing countries where the water was dirty was killing children. So we really do need to make sure that we're not getting vested interests too much involved.
So we've got Diet and Dry skin, the first two. The next two are Dogs and Dribble, we call it. And that's the hygiene hypothesis. And so we know that something to do with the microbial exposure is important, so we've talked a lot about the immune system but the other aspect of the immune system that's involved in training is the microbiome that we carry on our skin, in our nose, in our airways and in our gut.
So there are more microbes or bugs in our gut than there are people on this planet. And so some wise gastroenterologist said, 'We are basically a bag of bugs carrying around a body.' So our microbiome in our gut is a very important role to play in training particularly the innate immune system, that first defender. And the same with the microbiome on the skin. So we're starting to understand more about that with time. We know that having siblings and having dogs protects against food allergy. We just don't know what aspect of it is.
And then the fifth one is vitamin D. So we think vitamin D is a very important sunshine hormone to keep people healthy. You can actually ingest it. You don't have to have sunlight. So in Australia…
Norman Swan: In children or in the pregnant woman?
Katie Allen: Probably in both. We do know that we have changing rates of vitamin D deficiency in Australia, and when I travel internationally people say, 'Australia's a sunny country, why do you have problems?'
Norman Swan: So why should vitamin D affect this?
Katie Allen: Because it actually, just like we talked before about interferon, vitamin D actually gets inside the nucleus and affects more than 200 genes. So it's very important for the immune system. So we're actually doing a big study now of 3,000 infants, called Vitality, to look at immune health in the first year of life, particular in regard to a randomised control trial of vitamin D drops versus no vitamin D drops in the first year of life. Because in the northern hemisphere all babies are recommended to have drops, but also all of the dairy products are fortified. So we are the last country to really do that and we'd like to understand whether we need to do it or not to do it.
Norman Swan: And how does all this translate into treatment if you've already got an allergy?
Katie Allen: That's again, a very exciting stage of medicine at the moment. Because Australia has the highest burden of food allergy in the world, unfortunately. We do say we're the food allergy capital of the world. I'd like us to be the food capital of the world rather than the food allergy capital of the world. But we do know that we've had a very, very rapid response, both by our clinical fraternity and also the research fraternity. And we've been, the Australian Centre for Food and Allergy Research has been leading the way with regards to new treatments using oral immunotherapy to treat children particularly with peanut allergy, and we'd like to now move on to other areas like cow's milk.
Norman Swan: Just giving small doses of peanut to try to train the immune system.
Katie Allen: Train the immune system. And Professor Mimi Tang who I work with at the Murdoch Children's Research Institute has a ground-breaking new therapy that's in trial at the moment which is taking probiotics, which are a good form of bacteria, linking it to the small amount of increasing dose of peanut butter—or it's actually a peanut flour—and that's called PPOIT therapy, bringing those two aspects of those five Ds, the bacteria with the exposure, so diet and the hygiene hypothesis together to try and kick-start the immune system to tolerate the food.
Norman Swan: Can you please join me in thanking our fantastic panel, Nigel McMillan from the Menzies Health Institute, Queensland; Katie Allen from MCRI, and Mark Smyth from QIMR Berghofer were on our panel there. And that's it for the Health Report and me, Norman Swan for this week. See you next time.