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?
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.
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
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?
Another example done by someone else
How about another example done by someone else
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