Is microbiome the key? EAE says yes or does it say vaccinate?…Bacteria or myelin?

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We’ve all had enough of covid bloody nineteen but we can only report what is in the academic press. In our neck of the woods it has been a bad year for MS research…Our number of EAE experiments in 2020=0. It will be interesting to see how many enter the science literature in 2021.

Seems you want something different from COVID posts so here goes. New news from mousey central, its all microbiome. You can make your own mind. According to the authors it seems we have it all wrong, it is not Th17 causing autoimmunity that is the problem. It is the influence interleukin-17 (produced by Th17) has on the microbiome that is key. So what would you do vaccinate against myelin antigens or vaccinatte against the gut bactieria, or come up with new antibiotics?.

IL-17 controls central nervous system autoimmunity through the intestinal microbiome.Regen T, Isaac S, Amorim A, Núñez NG, Hauptmann J, Shanmugavadivu A, Klein M, Sankowski R, Mufazalov IA, Yogev N, Huppert J, Wanke F, Witting M, Grill A, Gálvez EJC, Nikolaev A, Blanfeld M, Prinz I, Schmitt-Kopplin P, Strowig T, Reinhardt C, Prinz M, Bopp T, Becher B, Ubeda C, Waisman A. Sci Immunol. 2021;6(56):eaaz6563.

Interleukin-17A- (IL-17A) and IL-17F-producing CD4+ T helper cells (TH17 cells) are implicated in the development of chronic inflammatory diseases, such as multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). TH17 cells also orchestrate leukocyte invasion of the central nervous system (CNS) and subsequent tissue damage. However, the role of IL-17A and IL-17F as effector cytokines is still confused with the encephalitogenic function of the cells that produce these cytokines, namely, TH17 cells, fueling a long-standing debate in the neuroimmunology field. Here, we demonstrated that mice deficient for IL-17A/F lose their susceptibility to EAE, which correlated with an altered composition of their gut microbiota. However, loss of IL-17A/F in TH cells did not diminish their encephalitogenic capacity. Reconstitution of a wild-type-like intestinal microbiota or reintroduction of IL-17A specifically into the gut epithelium of IL-17A/F-deficient mice reestablished their susceptibility to EAE. Thus, our data demonstrated that IL-17A and IL-17F are not encephalitogenic mediators but rather modulators of intestinal homeostasis that indirectly alter CNS-directed autoimmunity.

Anti-IL-17 treatment in humans wasn’t great and this paper suggests that a lot of the mouse work with IL-17 inhibition didn’t work. (I can buy this alot of it didn’t look very good) They say “IL-17 produced by T cells is not needed to establish CNS autoimmune disease and that a mechanism other than the absence of encephalitogenic IL-17 inhibits EAE development in IL-17 knockout mice (mice that lack IL-17)”, but this influenced by the microiome.

“In conclusion, our data support the notion that IL-17 is primarily
a barrier cytokine, vital for the maintenance of microbial homeostasis. Whereas these findings put previous discordant interpretations regarding the role of IL-17 in neuroinflammation into perspective, they foremost provide a conceptual advance in uncoupling IL-17 activity from encephalitogenicity. We believe that our data support further research efforts, which eventually will settle this long-standing debate in the neuroimmunology field. (I’m not sure there is much of a debate the naysayers are banished:-) From a translational point of view, our data on the integral relationship between IL-17 and intestinal health already have important implications in long-term therapies targeting IL-17 signaling in the context of chronic inflammatory diseases”.

There you go microbiome modification studies are the way to go. I wonder how many people have the same aim?

Right hand graph n=2 and n= 4. Yuck it ain’t worth reporting in this format. But one can see the reviewers did a good job….:-). The difference between green and grey = no difference (Mann Whitney) green and blue= no difference (Mann Whitney) as groups are too small. Do three poor experiments = one good one. I will leave it to you to decide, I know what I think.

So the EAE experiment points at the microbiome as the key. So where would you go microbiome or vaccine? Or vaccine against myelin or bacteria. It seems that myelin has been chosen.

A noninflammatory mRNA vaccine for treatment of experimental autoimmune encephalomyelitis.Krienke C, Kolb L, Diken E, Streuber M, Kirchhoff S, Bukur T, Akilli-Öztürk Ö, Kranz LM, Berger H, Petschenka J, Diken M, Kreiter S, Yogev N, Waisman A, Karikó K, Türeci Ö, Sahin U.Science. 2021 Jan 8;371(6525):145-153. doi: 10.1126/science.aay3638.

I have been asked over and over about this paper, even my mum rung be up to ask about it and so I have decided to talk about it abit more.

As a vaccine you want to give the vaccine before disease develops for it to work best. So we ask. Are we all going to volunteer to be immunized to limit the chance developing MS? You would need to immunize a thousand people to stop one person getting MS (At a rate of 0.1% of the population) unless you find people at risk and ask them to volunteer. So to stop 100 people getting MS you would need 200,000 people (half on vaccine and half on placebo). Then how long will the trial need to be to see an effect.

It will be much easier to do a study in people with MS.

If they are so confident that it will work, with the finance generated from creating a COVID-19 vaccine, then inventors can do it.

All I would say to them is “bung us a few bob” and the vaccine against MOG35-55 before committing to a human trial, one could easily suggests some experiments to do to make one more confident.

This study has been in the newspapers and it has got your hopes up. If the claims are correct. They have cured MS. You vaccinate against a myelin antigen and blocks immune responses in the CNS. The implication is that you don’t need to know the cause. Would this also stop immune responses to a brain infection but that’s another question.

However there is fact and there is fantasy. My fear. This is it is fantasy! You create an idea and suggest it works by a standard suppressive mechanism. This time it is via T cell regulators, so no surprise there then. In this context this is interesting science, but I am sure you don’t really need to care about the mechanism.

Let’s walk through the EAE experiments. The first experiement is what you want. No disease in vaccinated group (blue line on 0 to day 20) verses the light grey line.

Figure 3

Vaccine (arrow) just before disease onset (left, you can see it has worked within 5 days. Can you make a regulatory T cell in five days, yes, just about. Can you make a new T cell in 3 days..that really is pushing it, if you are starting from scratch. But the right graph shows that when you are injected at a score of 1 or 2, then it happens within 24 hours. So can you make T regulatory cells that quick?. Em…is this really the mechanism? You can turn disease causing cells off with anergy (a type of unresponsiveness) within 24 hours.

Next do it in a different strain, one that relapses what do you get. Well you get something different from that above.

So you say the vaccine against the causative antigen (green) works and so is a potentially pathogenic (blue/turquoise) antigen not used to induce disease. Great you don’t need to know how to stop disease from occurring. Problem is this shows that thefirst left hand figure above is not always the case, as it should be at zero, if it is reproducile. But it isn’t. The effect is not reproducible in this and other experiments (FigureS7). Animals are getting disease. So there are failures. How many?

Next, you ask why the upturn at day 25-30? (Above) Either some stranglers got disease or they were relapsing and so the vaccine was failing? Next you ask why have they been vaccinated six times? Six deliveries of vaccine by injection into the spaces behind the eyes, a procedure generally outlawed in UK about thirty years ago.

Give two doses (blue insnt’t enough). Do it twice a week

(blue two injections, green twice a week)

This is not vaccination which should require a few doses, this seems more like desensitization, with repeated antigen dosing. It can divert disease causing cells from goinginto the brain to go where the RNA vaccine-induced protein is going.

This is not good enough.

I know what can be done. Want an example?

Start with a single shot..oK there was a failure

Another example done by someone else

On single antigen treatment (Blue line) at the time of the arrow it was started after animals had disease

How about another example done by someone else

Here there was one treatment on day 29 or one treatment on day 58. This was started after disease had developed, It is reproducible. In another experiment start day 75 number of subsequent relapses 0/66 verses 37/48 controls. I know what I am talking about

What would MOG35-55 do in the above experiments…..nothing. Can this strain respond to MOG35-55 absolutely.

Is the approach interesting? Absolutely it is. Is it ready for prime time MS trials? I think it can work much better

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MouseDoctor

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  • On the gut part I’m pretty sure no one minds a healthy intestine whether or not it would affect your disease course. Maybe that’s why pomegranate is to potent on mice?

    For the vaccine part, why were the mice vaccinated that way if its illegal and downright cruel? Also, since previous studies are reproducible, why not build on that?

    • Illegal is only relevant to the country you are in. This the problem of the UK, we have a different legal framework to other countries, e.g. Dr Franklinstein sewed animals blood streams together, in the UK this is problematic in the USA they dont seem to care, so the work is done there. The horror shows I have seen when reviewing papers have gnererally originated in the far east. When reviewing I personally cannot accept anything I can’t do, without comment to the reviewer. In Europe work has to be done within the framework of 3Rs, was this. Now whilst you say yuck about injecing into the eye, the skilled person can do this very quickly and efficiently and may cause less discomfort that someone poking around your tail with a needle. Spare a thought for guinea pig users…they have no tail…There is a vein that you can see in males:-(

      At present we have a framework of where we can inject intravenously, the number of times is restricted, and the volume is controlled this is typically 5ml/kg (0.5ml per 100g = 01ml per 20g) therefore in this study the animals got 0.2ml so the mouse should be 40g. These would be very old males most mice are going to be 20-30g.

      “Since studies are reproducible why not build on that”…they have to either get the beasties and do the right studies or maybe give us the vaccine (and the cash to do it). I think I know what will happen. However if they routinely get this unreproducible guff, as they are following what other people do and using the same poorly reporducible systems, they think the result is good.

      I remember the guy who first crystalled one of the immunological molecules (a wow monent) doing an EAE experiment saying it was the great thing they had done…I guess Wilko Johnson was right…never meet your heros/heroines…P.S. I won’t say what he thought of Buddy Guy:-).

  • Utilise both approaches maybe
    A vaccine to make your immune system more tolerant to Myelin, clearly makes sense after the onset of MS if it can be done or is it just mRNA hype.

    And rather than antibiotics, would it be more beneficial to identify the good and bad bacteria’s, drown out the the bad by boosting the good? With a probiotic or maybe faecal transplant, but this will need constant work by the patient to maintain a healthy gut ie adequate fibre etc

    Regards

  • Since this mRNA technology is promising and tens of thousands of MSers have heard about this research and are hopeful for a breakthrough, why can’t there be a virtual conference with MS research scholars discussing concerns and ideas for optimizing these next trials. Have a discussion. Set it up.

    Who cares if THEY do it rather than give someone else cash to do it. Make sure anyone can do with this has the best chance of succeeding.

    There are Covid researchers tweeting out findings and ideas every day to save lives.

    Let’s approach the next few years of MS research with the same energy and spirit. Please.

    • There is a link to these posts attached to their papers and they can read them. I’ll send a letter and pre print. A conference will attract the people who will probably contribute to the failure of the approach.

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