Could nanoparticles cure food allergies and asthma?

Could nanoparticles cure food allergies and asthma?

This is the transcripts of the interview that I did with Dr Stephen Miller of NWU Medical School.  Here is the video of our conversation “Nanoparticles hold promise as the cure to food allergies and asthma.”

Healing Hacker: Hi, this is Denise with and today I’m talking with Dr. Stephen Miller of Northwestern University Medical School. Dr. Miller was part of the team of scientist that essentially took, in mouse models… took a peanut allergic mouse, or peanut allergic mice that were previously anaphylactic to peanut, and made them non-allergic. I’m hoping that Dr. Miller can shed some light on this study. Thank you for talking with me today Dr. Miller.

Dr. Miller: No problem, happy to do it.

Healing Hacker: I’m going to let you jump in and talk about your study, “Antigen-fixed Leukocytes Tolerize Th2 Responses in Mouse Models of Allergy.

Dr. Miller: Right. My lab for many years has been focused on developing what immunologist call tolerance based therapies for immune-mediated diseases. The primary focus of my lab, for many years, has been in animal models of multiple sclerosis and Type-1 diabetes. The study you’re referring to was initiated about 4 years ago in collaboration with Dr. Paul Bryce at Northwestern. He is an expert on allergy and animal models of allergic disease. What we tried to do when we set out to begin the study was to ask, ‘did the methodology that we develop that was successful in inducing tolerance for the therapy of autoimmune diseases… could we also do that in models of allergic disease?’

What these studies combined prove is that the tolerance strategy that we’re using, is effective.

The study involved taking leukocytes from mice, using a chemical reagent to attach peanut antigens to those leukocytes, and then administering those leukocytes by intravenous infusion back into the mice – either prior to the induction of food allergy, but more importantly, and more clinically relevant, to those mice who already had ongoing anaphylactic food allergies. The idea of the therapy is to expose the mice to antigen in such a way that it induces – well – that it turns off the immune response, rather than activating it. Basically what this study showed was that if we used the cells from the particular strain of mice, attached peanut antigens, and we’ve done it with egg antigens also, to their leukocytes and administered those back to the mice that had ongoing disease – we could actually protect them from the induction of an anaphylactic reaction.

Now I should point out that this methodology was successfully used in a Phase-1 clinical trial in multiple sclerosis patients. That’s an autoimmune disease not food allergy. But regardless, what the study showed was that it was safe to take human leukocytes from the blood, attach antigens to them, in the case of MS we used brain antigens, and reinfuse them back into the patients. We showed that it was safe to do this. And more importantly, we discovered that we could diminish some of the autoimmune responses that the patients had prior to therapy – even when they were retested one to three months after the therapy.

So the question is now, can we use a similar methodology to develop a safe and effective therapy for food allergy? Autoimmune disease and allergy are sort of on opposite ends of the pole. Autoimmune diseases are mediated by certain distinct types of T-cells that cause damage to self tissues. MS is an attack against the brain. Type-1 diabetes is an attack against pancreatic beta-cells. Rheumatoid arthritis is an attack against joint proteins. Allergies, on the other hand, are mediated by a totally different and distinct sub-set of t-lymphocytes that talk to other cells causing the production of IgE. IgE is the anaphylactic antibody.

What these studies combined prove is that the tolerance strategy that we’re using, is effective in animal models for the prevention and, more importantly, for the treatment of both autoimmune disease and allergic disease – both of which are immune-mediated disease processes.

Since the paper was published, we’ve developed a new strategy to induce tolerance in humans. Instead of using the patient’s own blood cells to attach either the autoimmune antigens or the allergic antigens to induce tolerance, or turn off the immune response, we now find that we can do this using manufactured nano-particles. These are composed of an FDA-approved polymer called PLG.

Just to give you some concept of this, PLG is what resorbable sutures are made out of. For example, it you have your kidney operated on, they cannot stitch it up with regular silk sutures because they’re going be irritating. The sutures would cause an immune response. Internal sutures are made of a nano-substance that’s biodegradable. That way after a period of time, the sutures will simply dissolve and go away. So we’ve developed methodology where we can make this PLG material into small microspheres that are about one-twentieth the diameter of human hair. To these we can either attach or encapsulate the auto antigens or allergic antigens – and we find we get the same, or even and in most cases, a better induction of tolerance.

We have a lot of interest from large biopharmas’ to partner with us in trying to develop this as therapies for these diseases. Before they were very reluctant to go down the road using the cellular therapy, because of the cost and complexity of that. We’ve formed a company now. Our goal with the company is to get FDA approval to carry out early clinical trials, hopefully in both autoimmunity and food allergy, to look at the safety and preliminary efficacy of treating those two types of diseases using tolerance based strategies.

Healing Hacker: When you say tolerance, can you explain the difference between tolerance and desensitization – because I think that’s a really important distinction?

Dr. Miller: Correct. The current therapies for allergy, and please remember I’m a basic immunologist, a mouse doctor, who does not treat either patients of autoimmunity or allergy. I’m telling you what I understand; and, some of it may not be totally correct. But, the current therapies for allergy involve repeated administration of low doses of the antigen that the patients is allergic to – like ragweed pollen or peanut extract or egg extract – whatever… And the purpose of that is to induce a particular kind of immune response that will absorb to these antigens and prevent them from engaging IgE in the allergic individual.  We call that desensitization because as a matter of fact, you’re shifting the immune response from one kind to the opposite kind – the kind that doesn’t cause allergy, in order to sop up the antigens, the allergens, and keep them from triggering the clinical signs of anaphylaxis and allergy.

…instead of switching immune response from an allergic kind to a non-allergic kind, we actually take the allergic kind and shut it off.

What we’re doing is called immune tolerance. What we found in our therapy is that instead of switching immune response from an allergic kind to a non-allergic kind, we actually take the allergic kind and shut it off. It’s a much more desirable way to go about it because the tolerance that we induce is mediated by particular kinds of cells called regulatory cells. These cells essentially maintain the ability for the individual not to respond to the antigen they are tolerized to for a fairly very long period of time. In many cases it may be for a lifetime. We don’t know how long it lasts in humans until we actually do that in clinical trials and figure it out.

There are multiple advantages to this. We think it’s safer. We can administer our antigen coupled cells, or nanoparticles, to individuals who are already allergic and carrying IgE antibodies with the net result being that we shut down the T cells, called Th2 cells, that help the IgE antibody to be produced. So, that’s the difference.

Healing Hacker: Talking about IgE, something that, and again I read this study and I’m not a scientist and I’m not a doctor, so correct me if I’m wrong, – but in the study my understanding was that you noticed in the mice that were treated, they actually had higher IgE levels than the mice that were not treated. How do you explain that?

Dr. Miller: Yes, that’s an interesting phenomenon. We’ve seen that same phenomenon if we substitute the nano-particles for the cellular therapy that was described in the paper that you read. The way that this works, is that despite the fact that we saw an increase in the amount of IgE antibody in the mice that we treated; they were still protected from the anaphylactic response.

The reasons are complex and we don’t understand them totally. What we think is that we actually induced regulatory cells – these special types of lymphocytes call T regulatory cells that prevent the mast cells from liberating histamine and serotonin, and the other anaphylactic mediators.

Now, you have to remember that, we have Th2 cells that talk to other lymphocytes; I don’t want to be more complex here. But, these cells are the ones that become plasma cells that actually squirt out the IgE. Our therapy is directed toward lowering the effector function of these T cells. In a patient or an animal that already has IgE, we wouldn’t expect to effect, at least in the short term, the levels of IgE. This antibody has a half-life of several months before it decays away. But we can knock out the helper cells that are required to continue to make the antibody. In the short term we’re protecting these animals against the anaphylactic challenge. Part of what we’re doing is inducing regulatory cells, in addition to knocking down the Th2 helper cells.

Now, if we would wait in these animals for a longer period of time, our expectation is, and this is yet to be proven, that the allergic antibody would eventually decay away because the T cell help needed to maintain it has been down-regulated.

The other way we’re thinking about treating allergies, including food allergy, is to combine our tolerance therapy – which is going to knock down the helper cells and increase the regulatory cells – with anti-IgE. This would be to prevent the existing IgE in participating in the release of mediators from mast cells.

By studying both of these models, we’ve come to understand how regulatory cells are induced and operate.

We would propose that the most effective short term treatment, that would have long-term protective affects, would be to combine our tolerance therapy with an anti-IgE. This would sop up the IgE already circulating in the blood stream and attached to the mast cells and basophil cells. That would have an immediate effect of protecting the individual. And in the long term, the induction of the tolerance would be maintained over a long period of time, hopefully months to years.

Healing Hacker: Got it. I’m just curious, what sort of, because you’re talking about that combo therapy with the anti-IGE. What sort of side effects have you noticed in the MS study with humans? What long-term, medium-term side effects did the treatment have?

Dr. Miller: That was the primary outcome measure over phase 1 clinical trials – safety…. We saw, believe it or not, no significant side effects at all from that process. I can’t tell you about the nanoparticles, which we think is the future, because we haven’t tested those in the humans yet. All I can say is that in mice we never observed any untoward effects of those particles. And we can treat animals multiple times if we want to.   You don’t need to because the therapy lasts for a very time as I mentioned before.

Healing Hacker: This was a mouse model of food allergy and the MS study was in humans. Is there anything that we haven’t discussed as far as what does the food allergy mouse model mean in human models?

Dr. Miller: Yes. That’s always hard too. We scientists always have this argument. When you’re modelling disease in a mouse model, or dog model, or chimp model, or whatever… the model is what its name implies, It’s a model. It’s not really the disease. But you really have to run these models to ask whether what you’re trying to do is safe and efficacious. And the FDA is going to require that before you can even hope to get the permission to try a therapy in humans. You do your best to use the most efficient animal models that you can use, that most closely mimic the human disease condition.

But you never know whether it really is going to do that.   And to be brutally honest, there are a lot of things that work in mouse models that don’t work in humans. And, that’s why we need to do clinical trials to find that out.

We’re encouraged by the robustness and the specificity, and the lack of side effects that we see in the animal models. We hope the same thing repeats itself in humans, but we’re never going know that until we try it.

Healing Hacker: Fair enough. Let me ask you another question. This is really about peanut allergy or as you mentioned egg allergy, even in MS you were taking brain antigen. This was one specific allergy, one specific antibody – What can we learn from these studies for the multiple food allergy sort of a spectrum? Is there anything that we can glean?

Dr. Miller: That’s a good question. Our approach would be that if somebody has peanut allergy, we would want to hit the T cells that are recognizing peanut antigens and shut those down and get rid of them. If somebody was allergic to multiple foods, as I understand it some people are allergic to multiple foods… perhaps shellfish, egg, and peanut… you would have to make multiple nanoparticles, or a couple of these cells with each individual antigen. So that’s the strength and, I guess maybe you would say, the weakness of our therapy.

The strength is – we’re highly specific. If we put peanut antigen into the individual, we’re only going to knockdown their peanut antigen allergic response. We’re not going to affect the egg antigen response in individuals that are allergic to both. In fact the egg antigen response would have be treated seperately, or at the same time with the combination of different antigens. We know at least in the autoimmune models, the MS models and mice, if we put nanoparticles in with two or three antigens, we can protect them from the disease induced by any one of those antigens.

You can imagine a situation where somebone with multiple allergies would be eventually treated with nanoparticles that are expressing each one of the allergic food substances that are responsible for their particular disease.

Healing Hacker: Got it. I am just curious about what can be learned from these studies as far as – what are the greater concepts that you’re learning about allergy, atopy, autoimmune diseases… Is there anything that we can learn from your studies about on how those things function? Kind of like a higher level vision.

Dr. Miller:   Absolutely. One of the questions with both the autoimmune and allergic diseases is – why are some individuals susceptible to developing those diseases and other people are not? I’m going to give one example – is there some sort of a deficiency in regulatory T-cells in an MS patient that somehow makes them more susceptible to developing the autoimmune disease? Or in a peanut allergic individual, is there some kind of deficit in there regulatory immune response that keeps most of us from getting autoimmunity or allergy? There are multiple reasons – genetic reasons why people are more predisposed to getting these diseases – there are environmental components. In allergy we know – the environmental component – it’s somehow ingesting that food stuff – whatever it happens to be.

In autoimmune disease, we know that there is a genetic predisposition. We also know there’s an environmental component. The only trouble there is that we have no idea what that environmental component is.   People think its particular genetic types that get infected with something at a certain period in their life that somehow interferes with what we call cell tolerance, or the activities of the regulatory cells.

By studying both of these models, we’ve come to understand how regulatory cells are induced and operate. We’ve come to learn a lot more about the intricacies of how that happens. That may lead to more effective and simpler ways to – in allergic individuals, increase the regulatory cells that stop the immune response. The same as in patients with autoimmunity, we’d want to increase the regulatory cells relative to the auto-reactive cells.

Now in cancer, you would want to do the opposite. That person is not making an effect in immune response to clear the tumor. You would want to lower the regulatory cells and increase the effector cells. By learning how tolerance works as an entity by itself, not really specific to any particular disease; we’re are going to gain a much better understanding about how to manipulate the immune response – either enhance it in terms of cancer or lower it in terms of treatment of autoimmunity and allergy.

Healing Hacker: Wow. Yeah, that’s very interesting to think about – because the regulatory arm is so important.

Dr. Miller: The Regulatory arm is absolutely critical – both arms are critical. And when you have one of these diseases, things are out of balance for some reason or another. That’s really important to understand – why and how we can overcome it.

Healing Hacker: One final question that just came to mind – I’m just curious, when you’re delivering these antigens intravenously – What’s the difference of getting them that way as opposed to consuming them? Why does delivering them that way induce tolerance but consuming them doesn’t?

Dr. Miller: That’s a great question and we understand a little bit about that. What we’ve learned is that when we intravenously infused these antigens, in the therapy of the paper that we’re discussing, or onto the nanoparticles… they pretty much work the same way. They direct that antigen to certain phagocytes that are in our spleen and liver. Once these phagocytes eat up the cells decorated with the antigens, or the nanoparticles decorated with the antigens, they talk to the immune system in such a way that they turn down the immune response rather than turning it up.

Our immune system is important. Obviously. It evolved to protect us against infectious diseases. Allergy and autoimmunity are just a bad side effect of a system that evolved to protect us from viruses, bacteria, fungus and infections. The immune system also deals with a lot of cells that die as a normal course of physiology. I’ll give you a particular example. Red blood cells… we have literally billions of them per cubic ml of blood.   But those red cells have a very short half-life. They age and die, what we call senescence, with an average life span of probably couple of weeks. The immune system is constantly seeing red blood cells and white cells that are dying as a normal consequence of how they’re produced and how they function. But the immune system has evolved ways to maintain tolerance of self. The last thing that we want to do is respond against dying white blood cells or red cells. And there are autoimmune diseases actually that attack our own red cells and white cells. Just about any cell in our body can be the target of some or another autoimmune disease. There are hundreds of them.

The immune system many millions of years ago evolved a way to eat up normally dying cells in such a way that it wouldn’t alert our immune system that its something to make a response against. And those cells that are responsible for the uptake and disposal of senescent red cells and neutrophils and other leukocytes in our circulatory system, are the cells that sit in the spleen and liver. And because of the way that we produce these nanoparticles, when we inject those intravenously, they are up-taken by those exact same cells. These cells then talk to the immune system in such a way that they turn off the response rather than turning it on. I s that clear?

Healing Hacker: I think so.

Dr. Miller: We are actually going into a system… into a procedure… that the immune system was smart enough to have evolved millions of years ago to protect us from responding against our own blood cell components. We’re artificially targeting those same cells for the treatment of autoimmune diseases which can either be in the brain or pancreas – or allergic diseases which can be taking place in the lung or gut or wherever….

Healing Hacker: I think I get it now and I’m just going to rephrase it back to you quickly. In an analogy, it’s almost like if you sneak into a restaurant through the back door and you put on a waiter’s uniform and go into the restaurant – you’re accepted – as opposed to you come in through the front door and you’re dressed in a way that’s inappropriate – and you’re rejected.

Dr. Miller: Exactly, you come in with a gun a mask.

Healing Hacker: Yes, exactly ok. I think that makes sense.

Dr. Miller: We have to get rid of dead and dying cells all the time. That’s hopefully done in a non-stimulatory non-immunogenic fashion. And for most of us, it is. For people with autoimmune disease or allergy, something has gone awry with that process. They are now making immune responses against their own cells, or proteins, or something that they eat. And we don’t want that to happen.   So we’re going back and using what the immune system was smart enough to have evolved over millions of years to deal with that kind of process, and using it to re-establish tolerance, either to the auto antigens or to the food stuffs.

Healing Hacker: Got it. Wow. I really appreciate your talking with me this afternoon. Is there anything else that I’ve missed that you feel it’s important for us to think about or to know?

Dr. Miller: I think that’s the gist of it. Where we go from here is – we formed a company based on this methodology of using the nanoparticles and we’re talking to a number of larger biopharmas’ to try to get them interested in investing in our technology. We are trying to develop this for the treatment of autoimmune diseases and allergies. The beautiful thing about the methodology is that it can be used for both – simply by changing an antigen from a brain antigen to peanut extract. We can treat multiple sclerosis on one hand, and hopefully food allergies on the other, using an FDA approved bio-polymer, what we call the universal toleragenic carrier. This has potentially far-reaching implications, but we’re not getting anywhere until we get investment to test this out in human disease.

Healing Hacker: Sure, sure. Thank you so much Dr. Miller and I hope that you keep us abreast of how things proceed with the nanoparticle study.

Dr. Miller: We can talk again sometime

Healing Hacker: That would be great.

Dr. Miller: Okay

Healing Hacker: All right. Thank you so much. Bye.


Further reading:
How the Immune System Works, Includes Desktop Edition