Is EAE a valid tool if studying MS

Mouse EAEers currently use myelin oligodendrocyte glycoprotein to induce disease, with which to study MS.

However, do people with MS respond to this protein
Papp V, Langkilde AR, Blinkenberg M, Schreiber K, Jensen PEH, Sellebjerg F. Clinical utility of anti-MOG antibody testing in a Danish cohort. Mult Scler Relat Disord. 2018 Sep 11;26:61-67. doi: 10.1016/j.msard.2018.09.010. [Epub ahead of print]

BACKGROUND: Anti-myelin oligodendrocyte glycoprotein (MOG) antibody (Ab) can be found in different immune-mediated inflammatory CNS disorders. The full range of clinical manifestations may not have been fully discovered yet.
METHODS:In a cross-sectional study 184 adults (age ≥ 16) were tested for anti-MOG antibody (Ab) with a cell-based assay. To define the relevant target population for anti-MOG antibody testing in a neurology clinic, we divided the entire study population based on the presenting symptoms and classified cases followed for multiple sclerosis (MS) according to the clinical features and response to disease-modifying therapy.
RESULTS:We identified eight (4.4%) MOG-Ab positive cases in the whole cohort. All eight cases had first manifestations suggestive of neuromyelitis optica spectrum disorder (NMOSD), but had highly variable disease courses and responses to therapy. This included a patient with chronic relapsing inflammatory optic neuropathy (CRION) responding only to therapy with infliximab. Four (3%) out of 134 cases followed for MS who tested positive for anti-MOG Ab showed atypical features and had poor response to therapy.
CONCLUSION:A broad range of clinical and radiological features of anti-MOG associated disorder was observed in a single centre. MOG-Ab testing should be considered in patients with an NMOSD phenotype and in MS patients presenting atypical features. The potential use of infliximab therapy for MOG-Ab disease should be further investigate

The simple answer is not many, as can be seen above. 

So first it was myelin basic protein and now it is MOG that the modellers think is important in MS, when both have been discredited. MBP could have been thrown away with 5 minutes of thought (I is not CNS restricted like MS, and there is little disease related extra activity) people with disease but it took countless trials. It was investigated because it was water soluble and easy for the T cell immunologists to make and was the mainstay until recombinant technology to make proteins and peptides came along. Proteolipid protein which is the major CNS myelin protein still does not get a look in because it is like brick dust and doesn’t dissolve in water so not great for the T cell immunologists unless you have a water soluble epitope. So myelin oligodendrocyte found favour, particularly because it was on the outside of the nerve and could be targeted by antibodies and most importantly it was the protein that best induced EAE in transgenic mice, which are on the C57BL/6 mouse background. MOG35-55 was found to induce disease and the rest we say is history. 

This history shows that MOG35-55 is not the main pathogenic epitope in MOG in C57BL/6 and that few humans with MS respond to MOG as this study shows. Indeed I have a HLA-DR type that doesn’t. yipee.

Furthermore, if people may antibodies to, it the disease is more neuromyelitis optica like. Therefore the protein has little validity as a target antigen MS.  

I am not aware of MOG trials yet, which is a good thing.

However it probably does not matter if the questions you are asking
are not about MOG the autoantigen, you can use the mice as tools.

Maybe we should all watch this video before using animals (CLICK HERE)

The 3Rs. Their definition, application and importance to your work from NC3Rs on Vimeo.

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  • Yay! First to comment. As ever,being a Mouse Doctor groupie, it has seemed absurd to me too the extent to which EAE and mouse studies have been used as a proxy for MS.

    This is despite having a daughter who is herself a Mouse Doctor!

  • In my admittedly less than learned opinion, it seems that EAE is a terrible model upon which to base MS research and in fact may have led to chasing far more false leads than not.

    What percentage of substances found to ameliorate EAE in mice have gone on to prove effective in treating MS in humans? I don't know the answer to this one, and would be eternally grateful if someone could supply the numbers, but I suspect the percentages would be quite small, probably less than 2%. Maybe far less.

    It seems that EAE may be useful in studying the type of damage done to the nervous system by ms (i.e. axonal degeneration and demyelination) but is fairly useless in studying the causes and possible remedies of the disease. If this is true, there is some value in studying the structural CNS changes wrought by EAE, but the massive emphasis on EAE research in the overall scheme of MS research seems at best misguided.

    I'm currently getting to work on a Wheelchair Kamikaze blog post tentatively titled "A Crabby Patient's Guide to MS Research", which would examine much of the folly and, in some cases, outright dishonesty (in the form of pharmaceutical company funded conflicted research studies, etc.) MS patients must navigate in trying to discern the wheat from the chaff when it comes to MS research as is is reported in the mainstream press and much of the MS related news sites.

    Your comments on any of the assertions I make above would be most appreciated as I prepare to write this proposed essay.

    • As of the publication by Vesterinen et al. 2010 there had been I think 1117 compounds tested in EAE and up to 2018 only two compounds (Natalizumab (or rodent equivalent) and copaxone) had their origins in EAE.

      The others came from elsewhere and have been tested in EAE subsequent to human data, but most MS agents made of protein do not directly work animals (rodents). E.g. human beta interferon does not work in rodents..however you can find a study where human interferon is used successfully in mice.
      Likewise cladribine does not deplete rodent lymphocytes, however we see papers reporting efficacy in EAE and I suspect more on the way. (Meaningless experimental wobble:-).

      If you look at the natalizumab data…it doesnt work well in rodents (e.g. search Kuchroo and Miller and a critical eye for Yednock et al 1992). The development was done in guinea pigs. The animal data with copaxone is incredibly weak and the agent was designed on false logic as I am pretty sure that myelin basic protein is not the autoantigen in MS. You get copaxone to work well by mixing it with the innoculum when inducing disease but otherwise it does not really work well.

      When I looked a few years ago it had not really been shown to work to stop relapses via the subcutaneos route. There are labs that report efficacy, but such labs have reported effects, but is it experimental "wobble".

      However, you cannot simply blame EAE. Neuros have played their part in the failure.

      There many clinical trials where candidates were tested in SPMS and they failed…no necessarilly because of the drug, but because the trial design was no good.:-(. Too small, too short, endpoint not responsivive, endpoint not fit for purpure, pwMS had placebo effect, pwMS did not take their medications (e.g. lamotrigine trial 50% of people did not comply, so trial doomed). Historically most immunomodulators from EAE were tested in SPMS and the trial failed because pw SPMS were never going to respond to the treatmet..

      Bad Pharma by Ben Goldacre has ideas about bad pharma

      Give me a nudge when you write your piece…

    • "Your comments on any of the assertions I make above would be most appreciated as I prepare to write this proposed essay."

      "The INSPIRE trial set out to investigate one of these following an anecdote that a person, who had MS but was treated with HIV-inhibiting treatment, did well.
      Was this a fluke or the beginning of a new era in MS research?

      You know the answer. Yep, the trial was not a success.

      This study looked at raltegravir, rather than looking at HAART, which is a cocktail of drugs used to inhibit HIV.

      Why? Because a company making raltegravir sponsored the study."
      Mouse Doctor

    • "However, you cannot simply blame EAE. Neuros have played their part in the failure."

      Somehow public think medical doctor are form of scientist..
      instead of a very long drawn out vocational program.

    • "Why? Because a company making raltegravir sponsored the study."

      No sponsor and no trial and therefore you can't even fail
      Mouse Doctor

    • "Somehow public think medical doctor are form of scientist..

      Some are, many are not.

      "instead of a very long drawn out vocational program".


    • Thanks for the info. Seems like my 2% estimate was a few decimal points to optimistic. Surprised to hear that Tysabri was developed in mice, will have to read the research. Interested to see how if it was originated in mice it was developed in guinea pigs. Kind of surprised that any of the monoclonal antibodies woodworking mice, as I would think that the markers targeted would not be present on mice cells, but perhaps I am not giving the little critters enough credit.

      Will definitely give you a nudge once I finish the article, think it may be slow going for a while as I have been battling some mysterious physical ailments above and beyond the MS for the last few months. Being sick on top of being sick is, as Mick Jagger might say, a drag…

      Thanks also to Adam for pointing out one of the fundamental dichotomies in medical research; much of it (most of it) is funded by Big Pharma, which has predispositions as to how, when, and if certain studies will be conducted. What a mess…

    • WK..another gold nugget for you..

      "Neurologist and research scientist Dr. Annette M. Langer-Gould says yes. When she read about Ocrevus’s approval in major media outlets, she was disappointed and described the reporting as “glowing, unabashed, buy-Roche-stock-now.” She left a comment on the New York Times story stating the drug is nothing more than an “expensive, overdosed version of Rituxan,” and she mentioned the need for more balanced news reporting. We reached out to her for more details."

      Here there was a headline that said "The Eagle has Landed"..yeah..Whatever

  • In HIV research they use monkeys with high fidelity to the human immune system. Why can't we use better models too? (I understand cost is one reason, but wasting money to mice is costy too since we have garbage researches)

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