Potential Therapies Targeting Memory B-Cells to Prevent Relapse and Progression in MS
Rajiv Jain, PhD, post-doctoral associate, department of clinical neurosciences, University of Calgary, talked about his presentation on T-bet+ memory B-cells in multiple sclerosis at the 2023 ACTRIMS Forum.
Rajiv Jain, PhD
Animal models are crucial in studying and identifying the contribution of different subsets of B cells in multiple sclerosis (MS). Associations with the B cells can be extracted to provide more context and insight on the disease. In developing a new model for studying autoreactive B cells in MS, Rajiv Jain, PhD, and colleagues were able to identify one population of B cells that seemed to be a driving force of the disease.
The findings, using experimental autoimmune encephalomyelitis models, were presented during a cutting edge development session at the 2023 Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum, February 23-25, in San Diego, California.1 In his presentation, he highlighted that T-bet+ memory B-cells are a pathogenic B-cell subset, the cells accumulate in the central nervous system (CNS), and are associated with CD4+ T cell and peripheral macrophage infiltration into the CNS. Notably, there are secreted factors from T-bet memory B cells that induce macrophage migration. All told, these results may open more opportunities for designing therapies that prevent the development of a relapse.
Jain, post-doctoral associate, department of clinical neurosciences, University of Calgary, sat down for an interview with NeurologyLive® at ACTRIMS to provide an overview of his cutting edge presentation. He shared his response to the observed secreted factors from T bet+ memory B cells and his general thoughts on future actions to take. In addition, he mentioned how his type of research could play a significant role in other aspects of MS and other related autoimmune disorders.
NeurologyLive®: What was the main question that you wanted to tackle in your research with B cell therapies in patients with MS?
We've known that B-cells are important in MS for a while now but the studies over the years have predominantly been trying to understand how B-cells contribute to multiple sclerosis. We found a variety of different molecules that seem to be involved in the pathogenesis. When I look at therapies that seem to be effective in the disease, it's usually blowing up an entire type of cell. I was thinking, “Well, there are a lot of different types of B cells.” For context, during my PhD, I was working in a lab studying how B-cells differentiate in particular to myelin auto antigens, which are in the context of multiple sclerosis as well. From that basic upbringing, I knew there are a lot of different types of B-cells, but no one's really answered which ones were the important ones. I wanted to begin tackling that question, but the issue you run into is, “How do we even begin disentangling this?”
There were some signs in the human data. It seemed, based on all the various different clinical trials that have been tried in MS, that one particular type of population of cells was preferentially affected by successful MS therapies. That was a population known as T-bet+ memory B cells, which are typically responsible for participating in secondary immune responses. If you're infected once with a virus, you get the generation of memory cells. If you're ever exposed again to that same virus, you would then get memory cells responding very quickly to the same virus. This provides you with that immunity so that you don't get sick twice. The issue you then run into is, “How do you even study those cells?” You would want to use something like a mouse model or something similar to that, but the problem is that mouse models don't really have a lot of these cells, and they're very hard to induce.
Based on of some of data from my PhD, it seemed like you can generate autoreactive B-cells, but then they die off very quickly. I had to develop a new model to begin to even disentangle this. I started off my postdoctoral studies by learning how to basically take B-cells and either turn them into one subset of B cells or another subset. Once I developed these cultures, I then did a very simple experiment of inducing autoimmune disease or experimental autoimmune encephalitis model in mice, which is supposed to simulate the inflammatory aspects of MS. We wanted to just inject those mice with various types of B cells and see what happens. When I injected them with the classical memory B cells, the conventional sort of memory B cells that we think of, I ended up getting nothing out of it. I started to wonder if maybe the model wouldn't work. But then I was like, “OK, we can try this other culture I did with these T-bet+ memory B cells.” The preliminary data showed they got this relapse, and it's all very exciting. Then COVID happened and it sat there for a year, and I couldn't even replicate it. For the last 2 years or so, I've been able to really push this project forward and now it seems really promising. I've identified at least one population of B cells that seems to be driving this disease.
What was your response to the T-Bet+ memory B cells inducing macrophage migration and is there any way to reverse this?
There are a lot of different avenues we can go down. Once you have a population identified as behaving differently than all the other B cell populations and once we know a bit more about the mechanism of how they're working, we can then know how to design a variety of different therapies. For example, my data would suggest that the cells are preferentially recruited into the brands of patients with MS relative to other B cell subsets. Presumably, if you could just block their recruitment, that would be one therapy mechanism. Also, it seems as though secreted factors from the cells promote the accumulation of other cells. Once I've resolved that a bit better, maybe just inhibiting that factor would be enough to prevent the development of a relapse. Or you could go down the route where a lot of the therapies we currently have simply blow up all the T-bet+ memory B cells. I don't know if that's viable yet but over the years, we'll do more and more research to really consolidate all those ideas and see which ones are valuable.
Do you feel that your type of research could play a key factor in some of the other MS aspects, besides relapses, that clinicians are starting to pay more attention to?
We definitely need more research to say this with any sort of certainty. But if I were to be extremely biased, and look at the progressive aspects of multiple sclerosis along with the relapsing aspects, and tunnel vision on this specific T cell subset, you could look at it and say, “The reason people go from relapsing remitting to progressive phase is just simply, when you're younger, you don't have enough T cells to consistently be above the threshold.” You could also say, “OK, these cells are also known as age associated B cells, because they just naturally accumulate with age, particularly in women, not so much in men.” But then when you get older, I can't say with certainty, as there is no data to support that yet. But work is in progress currently.
Why is it important to continue research efforts into autoimmune encephalomyelitis and how can this help our understanding of MS and other related autoimmune disorders?
The usage of animal models can be really helpful. One example is that there was a paper published in 2018 on the subset of B cell, these T-bet+ memory B cells. It looks promising, but there's no way for them to prove beyond a doubt that this subset contributes to disease. It was just some associations with some cells extracted from patients with MS and looks promising, but you don't really know. The only way to explicitly experimentally determine this is to use an animal model like this. I think the piece of work I put forward is the nail in the coffin that was needed for people to say like, “This isn't just something to pay attention to. This is like something we should actually be doggedly pursuing.”
Do you envision human studies starting to become more populated with this idea over the next coming years?
I think people already have. We walk around and look at some of the posters around here, we start seeing it popping up more and more and more. I definitely think that even without me having put this out, it was already people were starting to think along these lines. But I think now that this is here, it's going to be that nail in the coffin where we're now licensed to really care about it. It'll probably be something consistently phenotyped going forward.
In general, what have been your reactions and thoughts towards ACTRIMS as a whole?
It's been an outstanding conference. I did arrive late and didn't get to see everything but there are some unique therapeutic ideas coming out. There were some discussions around like the pros and cons but pursuing those different avenues. We have a lot of opportunities to have very good dialogue about these new potential therapeutic avenues. In that respect, I've enjoyed not just hearing all the pros, which we often hear a lot about, but also the potential cautions that might be important to think about going forward. So that before we veil or unroll these potential therapies, we'll have already thought through all the caveats.
Transcript edited for clarity.
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