An immune approach to treat multiple sclerosis

The immune system is the guard against pathogens; however it can be turned against us causing immune-mediated diseases. So far, there are several autoimmune diseases recognized, including inflammatory bowel disease and Multiple sclerosis (MS). Multiple sclerosis is an immune-mediated demyelinating disease affecting the central nervous system (CNS). In the United States, the prevalence of multiple sclerosis is 85 per 100000 people. To date, there are a few experimental models that resemble the pathology of multiple sclerosis, including experimental autoimmune encephalomyelitis (EAE) and theiler virus (TMEV). In EAE model, the demyelination is induced by the injection of foreign peptides which promote inflammatory response in the central nervous system. In the case of TMEV, the viral replication begins in astrocytes, microglia and macrophage in the grey matter. At a later stage of infection, the virus persists in macrophage in the white matter. The persistence is believed to initiate a prolonged inflammatory response from T helper cells, which ultimately leads to the demyelinating disease in the white matter. As the pathology of both mouse models closely resembles MS in humans, these two models are used extensively to study the role of immune system in promoting demyelination.

Related article: Fight against multiple sclerosis, a battle against demyelination

An important group of immune signaling molecules is cytokines. Cytokines are secreted by numerous cells. They are responsible for communicating between cells and directing the differentiation of T cells. In MS patients, IL-12 is locally expressed in the CNS. Its level is higher in the cerebrospinal fluid and plasma during active disease. Functionally, IL-12 is secreted by antigen-presenting cells. (see left)When antigen presenting cell recognizes a foreign particle through toll-like receptor 3 (TLR3), it turns on a cascade that phosphorylates IRF5. Phosphorylated IRF5 is then shuttled into the nucleus to activate the transcription of IL-12. Secreted IL-12 then binds to IL12 receptor on naïve T cells to induce the differentiation into Th1 cells and the release of proinflammatory IFN-g. There is also another cytokine found in MS patients that might be related to the induction of demyelination. Weiner et al. found a higher IL-23 level in the dendritic cells extracted from MS patients. IL-23 is a hetero-dimer that shares p40 subunit with IL-12. Despite the partial similarity between IL-12 and IL-23, IL-23 is functionally distinct inducing naïve T cells to differentiate into Th17 cells. So, if you are kind of confused at this point, all you have to know is that IL-12 makes Th1 and IL-23 makes Th17 cells. And both Th1 and Th17 are proinflammatory T cells. There is another subset of T cells that are anti-inflammatory known as the regulatory T cells, which counteract the inflammation. But we are not going to about regulatory T cells today.

So, how does this link to deriving an effective therapy for MS? IL-12 and IL-23 are inducing T cells to differentiate into proinflammatory T cells. What if we inhibit IL-12 and IL-23? Do we stop the inflammation? And indirectly stop the demyelination?

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The way to inhibit IL-12 and IL-23 is to generate antibodies against them. As I mentioned before, both cytokines share the p40 subunit. Thus, it seems feasible to treat demyelinating diseases with anti-p40 antibodies. Treating EAE models with antibodies against IL-12 and IL-23 works well. An antibodies-treated EAE mouse gets less demyelination.

There is a human clinical trial conducted by Segal et al. which they give a varying amount of antibodies (ustekinumab) against p40 to MS patients. However, they didn’t find a significant difference in alleviating demyelination in treated and placebo groups. It is discouraging to hear that antibodies against p40 don’t work on MS, as it has improved inflammation for other autoimmune diseases, such as psoriasis and inflammatory bowel disease. However, the researchers are trying to figure out the reason why antibodies didn’t work. There are a few suggestions made so far to explain this finding. One, the antibodies is 150kDa in molecular weight. It is possible that antibodies can’t cross the blood brain barrier to get to the CNS. Another possible explanation is that the recruited MS patients are in a much later stage of MS. Th1 and Th17 proinflammatory T cells are already recruited and accumulated in the CNS. So, blocking the induction of differentiation into Th1 and Th17 wouldn’t be a big help to MS patients at the late stage. Recruiting MS patients at an earlier stage of MS might give us a different result.

Deriving a drug for immune-mediated disease is a challenge, as we have to understand the cause of immune response. But we are closer than ever before as we continue to investigate the cause of MS.

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J Immunol. 2006 Jun 15;176(12):7768-74.

IL-23 is increased in dendritic cells in multiple sclerosis and down-regulation of IL-23 by antisense oligos increases dendritic cell IL-10 production.

Vaknin-Dembinsky A, Balashov K, Weiner HL.

Lancet Neurol. 2008 Sep;7(9):796-804.

Repeated subcutaneous injections of IL12/23 p40 neutralising antibody, ustekinumab, in patients with relapsing-remitting multiple sclerosis: a phase II, double-blind, placebo-controlled, randomised, dose-ranging study.

Segal BM, Constantinescu CS, Raychaudhuri A, Kim L, Fidelus-Gort R, Kasper LH; Ustekinumab MS Investigators.

Typo: corrected: cytokines are a group of molecules, not ‘one of the key immune molecules’ 09142012

4 thoughts on “An immune approach to treat multiple sclerosis”

  1. Thank you for this thoughtful post. I’ve just commented twice and each time WordPress at my comment. Bah!

    I hesitated before reading your post because I have MS and it does get tedious to see the ‘new hope’ stories which appear about once a week. So it’s a great relief that you didn’t write in that way.

    As well as having MS I have a PhD in parasitology, so I know a bit about the immune system. I say ‘a bit’ because, to me, it’s not the easiest scientific topic. One thing I’ll gently point out is that cytokines are a group of molecules, not ‘one of the key immune molecules’. You might like to look at the Journal of Interferon and Cytokine Research.

    1. Thank you for the comment. I am starting to plan my thesis on the TMEV model. So, this all comes from the readings from this week. And now I have to write a research proposal for a grant. Though I gotta say, writing a blog feels a lot better than writing a formal essay, especially when I get to interact with you!

      Thanks for pointing out the typo. You’re correct. Cytokines are indeed a group of molecules. They are not all pro-inflammatory, such as IL-12, IL-23. There are anti-inflammatory cytokines, such as IL-10 that are important in inducing regulatory T cells suppression.

      Immunology is definitely not the easiest topic. It is complex if you want to identify the cause of inflammation. In fact, the inflammation found in the EAE model can be lessened by the oral administration of polysaccharide extracted from the commensal bacteroides. But another study shows that germ free mice is less prone to EAE. So, it is still unclear what exactly contributes to inflammation in EAE and MS. But it is safe to say that it’s not just the local immune response in the CNS. The commensal bacteria in the gut also contributes to the inflammation in the CNS.

      1. Do you know, I’m hoping that you’ll use WordPress to chat about your research. Like you I find that blogging is so much easier than formal scientific writing. I’m intrigued by the ways people have started to do science on social networks and just now, I’m on the fence about whether this is a good thing. But here I am writing a science blog and reading yours. I’ve done a few WP searches on the keyword ‘science’, in fact, that might have been how you and I e-met.

        As you know my own WP blog isn’t about MS at all. I write about that, among other topics, on my personal blog on LiveJournal. I choose to keep my WP blog to the science that I love, avoiding the science of MS which seems to love me too much! But that needn’t stop me from reading your blog and finding it v interesting. I hope all goes well for you in your thesis writing. What a lot of work that is, says somebody who knows, but oh my, it’s so well worth it! You’re going to be Dr Cheng 🙂

        Good luck with your grant application too. I’m part of a team with one of those at the pre-proposal stage so fingers crossed. I hope you won’t let anybody pressurise you into neglecting your thesis though. That has to be the priority.

  2. I planned to talk about my research. It was one of the reasons why I started this site. But the problem is that I am not sure how to present it without the risk of exposing unpublished data. I assume one can talk about what kind of technique used in a day but explaining what is actually being extracted would be difficult. Anyway, if you have any good suggestion to go around that, let me know. I would love to talk about what I do during the day, but I don’t know how!

    Oh, grant application is killing me now. GAHH!

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