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Host – Dan Keller
Hello, and welcome to Episode Ninety-five of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.
Today's interview features Dr. Michael Levy, associate professor of neurology at Johns Hopkins University. When we met in his office, he told me about his work on the role of T cells in neuromyelitis optica, or NMO. Finding antibodies to aquaporin-4 is indicative of NMO. But when Dr. Levy used aquaporin-4 reactive T cells, they could induce NMO in a mouse model, giving a clue to the role of T cells in the disease, and possibly opening up a new therapeutic avenue.
Interviewer – Dan Keller
What's different about this approach than what has been thought of previously?
Interviewee – Michael Levy
In neuromyelitis optica, there is the thought that the disease involves an antibody, the anti-aquaporin-4 antibody, that that antibody is involved in causing the disease. And what we demonstrated in this model is that we could recreate the disease simply by developing T cells against aquaporin-4. It's the exact same target as the antibody, but instead of using the antibody to exacerbate disease, we use T cells. And it works really well and causes optic neuritis and transverse myelitis, just like in the patient.
MSDF
Can you briefly describe your method?
Dr. Levy
We raised T cells in mice that don't have aquaporin-4. These mice see aquaporin-4 as a foreign antigen and mount an aggressive immune response against them, and we harvest those T cells from that animal. And what we do is we polarize them. We basically turn them into more aggressive types of immune cells in a dish. And then we transfer those T cells to a naïve mouse that does contain aquaporin-4. And those T cells attack the aquaporin-4, and it does so only in the optic nerves and the spinal cord and also a little bit in the brain.
MSDF
But aquaporin-4 is distributed more widely than that in the body.
Dr. Levy
That's correct. Actually, there's a higher level of aquaporin-4 in the lung, stomach, kidneys, muscle. Many tissues contain aquaporin-4, but the T cells decide which aquaporin-4 to attack. They are a thoughtful type of cell, and for whatever reason, and this is true in the human, too, the T cells only decide to go for those specific tissues.
MSDF
How does a mouse with aquaporin-4 get to an age where you can actually get these T cells out of it? What's the use of aquaporin-4 if they really can survive without it?
Dr. Levy
It's amazing that these knockout mice, they don't have any aquaporin-4, are completely viable. There are some abnormalities in function under certain stressful conditions, like stroke or brain trauma, but for the most part, they live normal lives. They must have a good compensatory mechanism that they don't need aquaporin-4, and that's fortunate for us because we can create these animal models.
MSDF
When you transferred these T cells to wild-type mice, what did you see?
Dr. Levy
Eight days after the transfer, the first thing we noticed is that the mice started blinking and the eyes became sunken into the head, and that's a sign of severe optic neuritis. And then two days later, they had a dragging tail. And a day after that, their hind limbs were paralyzed, and that indicated transverse myelitis.
MSDF
What's the role of the antibody if you can induce the disease with the T cell? And does the antibody in itself without T cells have an effect?
Dr. Levy
We looked at that, and what we found is that the antibody by itself has absolutely no effect. But in the context of a T cell attack, it can exacerbate the disease, and it does lend specificity to the pathology when you look at it under a microscope. If you add the antibody, there is more aquaporin-4 damage, and it recruits compliment, which causes that damage. So that's really the role of the antibody.
MSDF
Can you induce the antibody without T cells? Essentially is aquaporin-4 a T-dependent antigen?
Dr. Levy
We think it is, and that's based on the type of antibody it is. The antibody in a human is what's called an IgG1 subtype, which is a T cell-dependent subtype. And that bears out in the animal models as well.
MSDF
So the antibody is really an enhancer in the disease as opposed to an initiator?
Dr. Levy
That's our thinking. It's not just an enhancer, but also a biomarker of the disease. And maybe in some patients, the antibody is not as harmful, but more of just a biomarker.
MSDF
What's the significance of these findings, especially as it relates to human conditions?
Dr. Levy
We're always looking for a new target to treat NMO patients, and there were some who were thinking that we should be targeting the antibody to try to either remove it or soak it up somehow. And maybe our model suggests that we should be targeting the T cells. And if there were ways that we could retrain or reeducate those T cells not to attack aquaporin-4 and create a really specific therapy, then we could avoid these broader immunosuppressive therapies that are necessary now to treat these patients.
MSDF
Since you have a defined antigen in this case, and I assume you can make some of it, do you have any hope of being able to induce high-zone tolerance using it?
Dr. Levy
That is our goal, and we've partnered with a company now to try to create a vaccine therapy using that antigen target. Again, in the same way that a T cell is turned pathogenic with this antigen, we can then retrain that T cell to be tolerized to it. And so we're hoping to apply that sort of technology to humans.
MSDF
Now you're coming in at a late stage of the disease. I mean, someone has to present with the disease for you to want to treat it. So really, you can't prevent it. This would be a therapeutic vaccine, not a preventative vaccine?
Dr. Levy
Correct. A vaccine therapy more along the lines of retraining than preventing and preparing. Correct.
MSDF
Now this applies to NMO, but what about applying it to MS? With NMO, you've got a defined antigen.
Dr. Levy
That's exactly right. And with NMO, there isn't what we call antigen spreading, which is where the immune system decides instead of targeting that one antigen, it's going to spread. The epitope is going to spread to other areas of myelin and maybe other components of the central nervous system. With NMO, the antigen is really focused on aquaporin-4, and so that's our advantage. And in MS, there are a lot more targets, and it's probably more of a heterogeneous disease. It would be harder to develop a vaccine therapy for MS.
MSDF
Where do you go from here? What's next?
Dr. Levy
Next is demonstrating that the mouse model responds to a vaccine therapy approach. We'd like to show that the T cells can be stopped, even when they're pathogenically targeting the aquaporin-4. Transferred into a mouse, we need to demonstrate that a vaccine therapy can prevent their attacks.
MSDF
Have you looked or demonstrated T cell receptors specifically for aquaporin-4 fragments?
Dr. Levy
We're looking at that now. We're looking in human subjects. We isolate their T cells, and we're looking for a response to certain epitopes of aquaporin-4. That has been done by other groups, but we're looking for specifically pathogenic epitopes now.
MSDF
Is there any thought towards some sort of suicide experiment where these T cells that have become activated could then be killed because they're proliferating?
Dr. Levy
There is a company in Houston called Opexa Therapeutics. They're doing something similar to that. They're picking out patients' T cells that are reactive against aquaporin-4 and inducing apoptosis so that when these T cells are reintroduced to the body, there is a tolerization. So it is kind of the same thing that you're suggesting. And they are hoping to launch a trial like this by next year.
MSDF
Is there anything we've missed or important to add?
Dr. Levy
What I'd like to emphasize again is that by focusing on the T cells, we can really hone in on the very upstream early event and really specifically treat…I don't want to use the C word to say cure, but it's really focusing on the source of the problem, rather than treating all the downstream consequences, which is what we do now. So I think our approach has that specific advantage.
MSDF
An advantage over a more global nonspecific immunosuppression?
Dr. Levy
Exactly, which is what we're doing now.
MSDF
Very good. Thanks.
Dr. Levy
Thank you.
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MSDF
Thank you for listening to Episode Ninety-five of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.
Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.
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For Multiple Sclerosis Discovery, I'm Dan Keller.
