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Simplifying the Science of NMO – Breakout Session – 2018 NMO Patient Day

Dr. Michael Yemen:
Thank you very much for being here. We talk a lot about a lot of different stuff, but I hope you realize it’s all for you. This is really all for you. One of the things that I’d like you to know for you is that you already know what I’m going to talk about today, in way more detail than you think you know. Because a lot of this is intuitive. There’s a lot of acronyms and jargon and stuff like that that’s used in NMO as there are in many conditions and diseases and stuff. We’re just going to peel off the jargons and the acronyms, and you’ll see that the basic functions here are very understandable. I even would predict that you’ll be able to go teach other people about NMO. That’s our goal today. How’s that?

Dr. Michael Yemen:
Okay. A couple of fundamental things about the immune system that are really very cool. Once you get that, it’ll explain a lot about a lot of things. First, your immune system is constantly changing. I mean, constantly. Let me just ask you to do this. Take a deep breath and hold it for a second. Okay. Now let it out. This is not about meditation. This is about the fact that you just inhaled maybe about a million spores. Okay. Now you might be thinking, “Hey, we shouldn’t have done that.” Well, you could stop breathing, but the point is, every moment of every day, your immune system is seeing things. It is constantly monitoring, sensing, deciding. That’s a really fundamental concept, that your immune system constantly changes. It’s not static. You’re not born with the same immune system as you have today. By the way, tomorrow, it will be different than it is today. Are we okay with that? Do you believe that?

Dr. Michael Yemen:
Okay. Every time you shake someone’s hand, every time you touch a door knob, every time you rub your eyes, every time you go to a park and breathe in pollen and stuff, constantly changing. Okay. Here’s the other thing that’s really amazing. The genes that encode the ability of your immune system to see things in the universe that might be bad, is essentially infinite. The genes in your immune system deck can be shuffled over and over and over again, so you have the capability of making antibody to almost anything. Let me give you an example. You have the capability of making antibody to Jupiter moon dust. Do you believe that? You can make antibody to Jupiter moon dust, but here’s the miracle side of this. You will not make antibody to Jupiter moon dust unless you are exposed to it. It’s the difference between can and do. We good with that? In other words, your immune system has crazy infinite potential, but it only actually reacts to things that you encounter.

Dr. Michael Yemen:
Everybody okay with that? Okay. I mean, that’s a beautiful get-your-head-around-it kind of a thing, that is the topic of a long cocktail party or something. There’s a lot to that. You can do almost anything with your immune system, but you only will do something with it based on what you actually see, your immune system sees. Okay. Now let’s, with that, focus on a few definitions. Because, just like learning any language, the first thing you do is you learn the vocabulary. That’s all we’re going to do for a few minutes. Because, once you understand the concepts that we just talked about and you learn the cast of the play, you are going to say, “Hey, I already knew that.”

Dr. Michael Yemen:
All right. Let’s work from right to left. Over here is an astrocyte, called an astrocyte because if you look at it under the microscope, it has a body like a cell, but it has a lot of dendrite-type pieces of the cell extending from … Like a star. It’s brilliance, that’s why they’re called astrocytes. Astrocytes have aquaporin-4 on their surface. Aquaporin-4 is expressed on the surface of astrocytes. You okay with that? Astrocytes are in the central nervous system, the brain, spinal cord, optic nerves. Over here is the central nervous system. Between the central nervous system and everything else in your body, for this case, let’s call it the bloodstream, is a barrier called the blood brain barrier. It’s made of these cells that are called endothelial cells. You don’t really need to know that. Just know that normally, there is a tight seal between the periphery and the blood brain barrier. Because, the brain and the spinal cord and the optic nerves are what are called a privileged compartment. You don’t want just anything getting in there. This is your brain, after all.

Dr. Michael Yemen:
Okay. Central nervous system, blood brain barrier, everything else. Let’s think of it as the bloodstream. Okay. Here’s a quick test for you. When somebody draws blood from your arm, where are they taking it from on this diagram? Right here. The needle goes in your arm, the periphery. Blood is drawn, cells and molecules and stuff go into the blood. Is there ever a time when a needle is inserted into the central nervous system?

Dr. Michael Yemen:
Yeah, exactly. Lumbar puncture, it’s called. It’s where you get cerebral spinal fluid. So you can put needles in all different places. You got to be careful. But we’re really going to talk about what’s happening on both sides of this barrier. Are we good with that? So far so good? Okay. Now let’s talk about some cells and some molecules. A protein that is seen by your immune system is called an antigen. Anti, meaning mount an anti response. Gen, meaning the origin of. Antigens cause your immune system to mount a response. It doesn’t mean it’s bad, it just means it’s a response.

Dr. Michael Yemen:
A dendritic cell is one kind of cell that presents antigens to other cells in the immune system. Dendritic cells are like sentinels. They’re like monitors. They go around the body and they say, “Okay, I’m checking things out. Yep. I’ve seen this before. It’s normal. Not going to react to it.” They keep cruising around and they see something else, and they say, “Okay, I’ve seen this before. It’s self. Fine. I’m not going to react to it.” But some times dendritic cells see things that they perceive as foreign, as non-self. When they do that, very much like a fisherman after catching a fish might mount it and show it as a trophy, dendritic cells, when they see antigens that are unusual, they grab them and process them and put them on the surface of their cell like a trophy. We’ll come back to what they do with that in a second. Okay? So dendritic cells are a type of antigen-presenting cells, they just present proteins to other cells in the immune system.

Dr. Michael Yemen:
Okay? All right. You’ve heard of B and T cells, and you’ve heard there’s different kinds of B and T cells. Some are good. Some are bad. What does all mean? Well, let’s consider that there are normal B and T cells. In fact, they’re called naive B and T lymphocytes, because they haven’t made any decisions yet about what they’re going to do. There are autoreactive T cells and B cells. These are cells, just like their name implies, react to self. They are autoreactive. Do you think autoreactive T-cells are good or bad? They’re kind of bad. On the contrary, regulatory T and B cells, in NMO at least, are good. Because they suppress inflammation. They regulate inflammation. They’re called regulatory T and B cells. All right, so you’ve got naive T and B cells. You’ve got regulatory T and B cells. You’ve got autoreactive T and B cells. Are we okay with that?

Dr. Michael Yemen:
All ready you know from the lymphocytes out here that there are some that can tell the difference between self and non-self really well, but there are others that might not be so good at it. And if they make mistakes, they’re going to see your normal tissue as foreign and they’re going to cause problems. We’ll come back to that. Also in your periphery, so when you get your blood drawn and you see the labs, it says, “Total white cell count,” and total stuff. These are the leukocytes, neutrophils, eosinophils, macrophages among others. These are inflammatory cells. When they get called in, they are going to cause trouble. They’re like bouncers in a bar or something. This stuff compliment. Compliment sounds like it’s one thing, but compliment is a combination of about 40 different proteins that act like a domino effect. If one of them gets activated, then it activates the next one, and the next one, and the next one, pretty soon you have this chain reaction.

Dr. Michael Yemen:
So compliment is a set of proteins that is normally inactive. Something has to turn it on. And when it turns on, it becomes inflammatory. You get it right? Here’s the periphery minding its own business. Here’s the astrocyte minding its own business. Here’s the blood brain barrier minding its own business. All before NMO. Here’s where it gets both interesting and mysterious. I just want to tell you a little quick story about this that is hard to believe, but it is true. Where are your blood cells made? Just generally, bone marrow? All of your blood cells are made in your bone marrow. Where is your bone marrow, by the way? Most of the blood cells that are relevant to the immune system, and in fact, most of the blood cells come from the long bones of your femurs and the crests of your hips, the iliac crest. That’s where most of your bone marrow is.

Dr. Michael Yemen:
Now, you have marrow in every one of your bones, but that’s where most of your bone marrow is, in those tissues. Now, here’s the crazy part that you may or may not believe, but I hope that you believe it is true. T cells are called T-cells because, for reasons that we don’t have time to talk about today, they find their way from the bone marrow, circulate through the blood and go to the thymus. Thymus. That’s why they’re called T cells. The thymus is a gland that wraps around your esophagus. It’s about as big as your fist at its biggest point. It’s much smaller when you’re young and it’s much smaller when you’re older. The thymus is the T cell university. T cells go to the thymus and they undergo two tests. The first, can you react to an antigen at all? In other words, if a dendritic cell shows you, as an antigen-presenting cell, if a dendritic cell shows you an antigen, can you recognize that it’s an antigen? That’s test one.

Dr. Michael Yemen:
Test two is, can you tell whether that antigen is self or non-self? That is, can you tell the difference between normal and abnormal? You got that? So T cells that come from the bone marrow mysteriously find the way to the thymus and undergo one test. If they pass that test, they graduate to a different part of the thymus. If they pass that test, guess where they go. They go to the lymph nodes in the periphery. Do you ever notice why your lymph nodes expand when you get sick? You will know why that happens in just about 20 seconds. Okay. We got that, T cells come from the bone marrow? They’re naive. They don’t know about it. They’re just like, “Okay, I’m a T cell trying to find my way.” They go to the thymus. They undergo two tests that assure that they can respond to something and they can tell whether that’s something is good or bad. Similarly, B cells go to the spleen. We’ll talk about that another time.

Dr. Michael Yemen:
Okay. You know the players now and you know the basic concepts. I bet you, you’re going to see now that you know a lot more than that. For some reason that we do not fully understand, dendritic cells, antigen-presenting cells, come from the periphery when the blood brain barrier opens for reasons that we don’t understand and enters the central nervous system. And they say, “Mr. Astrocyte, there’s something about your surface that I just want to check out.” Now remember, this is where the aquaporin-4 is. Dendritic cells, these are the sentinels. These are the cells that are checking things out, is it good or bad, right or wrong? There’s two ways that aquaporin-4 on your astrocytes can be perceived as abnormal. One is if it really is abnormal. If it’s mutated, if it’s being processed funny and it’s being put into the cell membrane of the astrocyte funny. There’s lots of ways that can go wrong. Or your astrocyte and aquaporin-4 can be perfectly normal, but your antigen-presenting cell can see it as abnormal. Are we good with that? Okay.

Dr. Michael Yemen:
Remember, your B and T cells that are naive are hanging out in your lymph nodes. When your antigen-presenting cells sees something that they think is abnormal, they take it back to your lymph nodes, where are they talk to T-cells. They present the antigen to the T cell in your lymph node, which is why your lymph nodes inflame, basically. Here’s where things get very focused on NMO. If a naive T cell converts from this presentation to an autoreactive T cell, now this is a T cell that is going to react to your own self. More specifically, it’s going to react to what it was presented. What was it presented? Aquaporin-4. It’s going to go into the central nervous system and say, “This astrocyte has something wrong with it.” Are we good there?

Dr. Michael Yemen:
If you have a autoreactive T cell that is saying there’s something wrong with a host cell, a cell that should be normal, it will do a lot of things, including call in B cells. What do B cells do? B cells make antibody. They will only make antibody if the T cell says, “Okay.” Now you’ve got an autoreactive T cell that is saying, “Hey, there’s something wrong with your astrocytes.” That then tells a B cell, “Hey, you got to start making a bunch of antibody to the stuff that I’ve recognized,” which is aquaporin-4. Now all of this antibody comes out of the B cell and it binds all over this astrocyte. If you have antibody that binds very tightly to a protein, it will trigger the activation of compliment. Now compliment comes rushing in and fixes to the astrocytes, aquaporin-4.

Dr. Michael Yemen:
When compliment fixes, that is, binds to, so if you’ve got a cell and you have now antibody binding to it, that in turn triggers compliment to bind to that. When complement binds to an antibody, it becomes active and activated compliment floods back out into the periphery as sort of a molecular beacon. And what does it do? It recruits all the inflammatory cells. Neutrophils come rushing in. Eosinophils come rushing in. Macrophages, big eaters, literally, come rushing in. How do you think the astrocytes are going to hold up to this inflammatory infiltration? Because now you’ve got all these cells that are inflammatory thinking there’s something foreign, something abnormal going on here. These cells are one way go-get-it-and-kill-it cells. Just to give you an example and not to be too direct or anything but neutrophils, when they accumulate in your skin, chasing down a bacterium, for example, they become pus. They’ve gone there. They’ve killed the bugs. They die there, and that’s pus.

Dr. Michael Yemen:
Same kind of thing can happen in here. You’ve got this massive infiltration of inflammatory cells. That is the pathogenesis of NMO because, if you then through all these reasons, kill the astrocyte, astrocytes are what take care of neurons. Then the neurons start to die. And when you have macrophages running around, big eaters that have got nothing better to do now, they will start chewing on myelin, the insulation of nerves, and you will get demyelination. If you think about it this way, it’s not that complicated. One thing leads to another.

Dr. Michael Yemen:
Just like, I mean, think about if you’re in your house and you hear something out in the backyard or the alley or something. What are you going to do? You’re going to call, “Hey, could you get a dendritic cell to come over and check things out? A dendritic cell comes in, says, “Yeah. Okay. I checked it out. There’s something out there. One of the trash cans has got something. Man, I’ve never seen that before.” Dendritic cell says, “I got to take this back to the station. We’re going to check it out.” The T cell station. T-cells say, “Whoa, where’d you find that? We’re going to go check it out.” It’s that kind of a situation that is intuitive to you. You know this already, is my point.

Dr. Michael Yemen:
Now, before we go on briefly to the targets of therapy, I just want to make sure you totally understand this. This is an astrocyte that makes aquaporin-4. Antibodies made in this scenario will be anti aquaporin-4 antibodies. A person who has this scenario going on will have anti aquaporin-4 positive NMO. I’m just going to use this cell in a different way for a second. If this cell, instead of being an astrocyte, is an oligodendrocyte, same process, same mistaken identity. If this is an oligodendrocyte, what kind of antibody is going to be made to this? Remember, oligodendrocytes, they don’t express aquaporin-4. They express MOG. What kind of antibody will be made here? Anti MOG. Thus, the pathogenesis of anti MOG positive disease. It’s one or the other. You don’t have both. That’s the crazy thing about NMO. Sometimes the immune system sees an astrocyte or aquaporin-4, and says, “Wow. I’ve never seen that before. We’ll get that.” Sometimes, it leaves that alone and chases down something that’s right next to it. MOG on a cell that’s right next to an astrocyte.

Dr. Michael Yemen:
Okay. Now, lastly, on the other side of your map, and you can take a look at this when you have time, tell me about therapy. Tell me about, let’s just take them by alphabetical order. Tell me about eculizumab. What does it target again? It targets compliment C5 protein. Eculizumab takes this part out of the equation. You can be making antibody, but if it doesn’t activate compliment, you don’t get these guys coming in because there’s no beacon. So with eculizumab, the theory is, sorry, you can be making all this stuff, but the inflammatory cells will not be drawn in because there’s no compliment activation. Because you’ve neutralized compliment with the antibody, to compliment.

Dr. Michael Yemen:
What about, let’s put all this back together here. What about a rituximab? What does it target? The B cells. You take this out, no antibody. B cells make antibody. No antibody, no compliment fixation. No compliment fixation, no leukocyte infiltration. You guys get this. Okay? Let me give you one that’s a little bit harder. Let’s see. Wouldn’t it be nice to not have to treat at all? Wouldn’t it be nice to say, “Hey, we’re treating the symptoms here. Can’t we treat the cause?” What cell would you remove if you wanted to treat the cause?

Audience:
TAR

Dr. Michael Yemen:
Absolutely. Let’s get rid of this. None of that, no B cell comes in. No B cell, no compliment. No compliment, none of those guys. Back to normal. How do we get rid of an autoreactive T cell? Tolerization. Rebooting the immune system to teach these cells aquaporin-4 is not bad. It’s not a bad thing. It’s supposed to be there. It’s a little bit like an allergy shot. You know how that works? You treat kind of with the thing that is causing the problem and it causes something that’s known as energy. Allergy is a hyper immune response to something, too much. Energy is too little. In fact, what happens in energy is that the immune system just says, “I’ve seen that enough. I’m not worried about it anymore.” That’s one way to tolerize.

Dr. Michael Yemen:
Another way is to treat the autoreactive T cells in a way that they become actual targets of the immune system. The immune system takes them out like an autoreactive T cell vaccine, which now if you target these cells as being foreign, the immune system is going to take them out. Then perhaps the most sort of extreme example of tolerization is where you take all of these things off the board. What’s that called? It’s called bone marrow transplant. You take them all off. You basically remove the person’s immune system, which by the way, it can be done in a much gentler and less life-threatening way than it’s ever been done. Then you replace it with healthy immune system cells that do not have auto reactivity. Then what happens? Then you got a central nervous system and a blood brain barrier and all this stuff over here, once it comes back, that’s normal. And you stop therapy, forever.

Dr. Michael Yemen:
That’s tolerization. That’s why we want so much to develop ways to tolerize. Because, even the best medicines, if you take them for long enough, are going to have effects that you don’t want. Okay. I know that might sound complicated. I hope it didn’t sound complicated. I hope you realize that you know way more about this than maybe you thought you did. Questions? Please.
Audience:
Northwestern I thought was doing a study with a bone marrow transplant, are they, I mean, in the mix of that I think I heard a couple of people, one of the patients there that died had the transplant from Northwestern.

Dr. Michael Yemen:
Yep.

Audience:
What’s going on with that?

Dr. Michael Yemen:
If you look on clinicaltrials.gov, you will find that study is still active. They’re still recruiting. For people who have relapses, despite trying many different therapies, I mean, the risks of that process are now much lower. The benefits are now much higher. It’s an option that you should really think about. Yeah. Other questions? What do you think? You could probably go tell somebody about this now. I mean, it’s a little bit like the leg bone is connected to the ankle bone. Because you say, “Well, hey, the antigen-presenting cells got to talk to the T cell. And the T cells got to be the one that approves the B cell to make antibody. And the antibody binds to aquaporin-4 and that causes compliment fixation, which just draws in all these inflammatory cells.” You got this.

Audience:
So all TNB cells are not bad?

Dr. Michael Yemen:
That is correct. That is correct. All TNB cells are not bad, which is why when you use a drug that removes everything indiscriminately, it might have beneficial effects, but it’s also going to have some non beneficial effects. Yeah. Please. Hi.
Audience:
There was quite a little bit talk about your [inaudible 00:32:15] genetic aspect to NMO.

Dr. Michael Yemen:
Yup.

Female:
If that’s the case, will that type of therapy actually work [inaudible 00:32:25] not take over?

Dr. Michael Yemen:
It depends. Yeah. It’s a great question. It depends on the genes that you’re talking about. I’ll use an example. You know the exciting breakthroughs in cancer recently that are called the checkpoint inhibitors? Maybe you’ve heard of something called Yervoy or ipilimumab or stuff like that. What those drugs do is they turn off the brakes of the immune system, and they allow T cells to chase down cancer cells. When, before that treatment, they wouldn’t. They released the brakes. If the genetic mutations are in the checkpoints, even upstream of the bone marrow, then that could be a problem. You might not be able to solve it with a bone marrow transplant, but the immune system knows what it’s doing. Remember we talked about the two exams that T cells have to undergo.

Dr. Michael Yemen:
As long as the thymus is intact, if you perform a bone marrow transplant, there’s every reason to believe that the thymus will educate the new T cells in a way that they do not see aquaporin-4 as foreign. Even if there are mutations elsewhere. So I guess in getting back to your question specifically, there are some genes that are believed to be related in NMO, and they have to do with the genes that encode the T cell receptors and the receptors in the antigen-presenting cells. In other words, all the molecular machinery that allows for these handshakes between cells, it’s very likely that it’s not just one gene, that it’s what’s called polygenic. That there’s multiple minor dysfunctions rather than one huge genetic problem.

Dr. Michael Yemenl:
So if you look at the cases that have been transplanted, the bone marrow transplants of NMO, there’s a very high proportion of cure. I think that’s because the immune system knows, in ways that we don’t fully understand yet, how to teach T cells when they come out of the bone marrow that’s been replaced, to deal with mutations if they exist. I know that’s a little bit of a complicated answer, but bottom line is, if you look at the results from bone marrow transplants, it’s probably like a 75% cure rate now. The downside is that, when it doesn’t work, it kind of goes bad in a bad way. So it’s kind of an all-or-none kind of a deal.

Dr. Michael Yemen:
But if you’re talking about seeing a person going from unable to walk to able to run and walk, bone marrow transplant has done that already. It’s not for everybody though.

Audience:
So they test for that genetic level before they do the?

Dr. Michael Yemen:
Oh yeah, sure. Those are the screens and the matches and everything that are really all part of that. Yeah. Okay. Anything else? I know we’re getting to the time we got to get going. I hope it’s been helpful. I think you already know more than you think you did about NMO and aquaporin-4 and MOG. Please.

Audience:
When you were talking about how the different therapies react to the body, what about plasma trasnplant?

Dr. Michael Yemen:
Plasma exchange?

Audience:
Yeah.

Dr. Michael Yemen:
Plasma exchange takes all of this stuff out, pushes the cells to one compartment and the plasma to another compartment, keeps the cells, replaces the plasma. It’s intention is to get rid of the molecules in the blood, not the cells. The idea is that the antibody and the compliment and stuff, all the molecules are there. And so, the goal of plasma exchange is to get rid of the molecules, not the cells. On a related note, IVIg is introducing antibody from the outside. This is pooled, normal, healthy IgG, immunoglobulin G. That in theory is that those antibodies go in and they either out-compete the bad antibodies or they bind to the bad antibodies and neutralize them.

Dr. Michael Yemen:
So one way or another, you’re either taking antibodies out with plasma exchange or you’re putting good antibodies in with IVI. Either way, you’re trying to stop this process over here from happening. By the way, just one last thing. I’m sorry but, we talked about everything requires a breach in the blood brain barrier. Why not target this? There is a drug that will do that. It’s called bevacizumab. It’s used for macular degeneration. People get shots in their eyes. Well, it does seal the blood brain barrier. We’ve tried it in NMO and it looks like it works.

Audience:
What’s it called?

Dr. Michael Yemen:
Bevacizumab.

Audience:
It’s hard to hear

Dr. Michael Yemen:
Bevacizumab. B-E-V. Yeah. It’s called Avastin, is its name. Yeah. Anyways, it’s a very exciting time. I know this will sound crazy, but there has never been a better time to have NMO. Because, there’s a lot of stuff coming down the line. You heard about the clinical trials. Those are nearing the finish line for some of them. That’s going to provide the next step for the next better drugs and, ultimately, tolerization. That’s where we’re headed, and we really appreciate you helping us with that. This is all for you. Okay. Thanks a lot. We’ll see you downstairs.

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