Monday, 24 October 2016

Getting the Right Models

Lassmann H, Bradl M.Multiple sclerosis: experimental models and reality. Acta Neuropathol. 2016 Oct 20. Review.

One of the most frequent statements, provided in different variations in the introduction of experimental studies on multiple sclerosis(MS), is that "Multiple sclerosis is a demyelinating autoimmune disease and experimental autoimmune encephalomyelitis (EAE) is a suitable model to study its pathogenesis". However, so far, no single experimental model covers the entire spectrum of the clinical, pathological, or immunological features of the disease. Many different models are available, which proved to be highly useful for studying different aspects of inflammation, demyelination, remyelination, and neurodegeneration in the central nervous system. However, the relevance of results from such models for MS pathogenesis has to be critically validated. Current EAE models are mainly based on inflammation, induced by auto-reactive CD4+ T-cells, and these models reflect important aspects of MS. However, pathological data and results from clinical trials in MS indicate that CD8+ T-cells and B-lymphocytes may play an important role in propagating inflammation and tissue damage in established MS. Viral models may reflect key features of MS-like inflammatory demyelination, but are difficult to use due to their very complex pathogenesis, involving direct virus-induced and immune-mediated mechanisms. Furthermore, evidence for a role of viruses in MS pathogenesis is indirect and limited, and an MS-specific virus infection has not been identified so far. Toxic models are highly useful to unravel mechanisms of de- and remyelination, but do not reflect other important aspects of MS pathology and pathogenesis. For all these reasons, it is important to select the right experimental model to answer specific questions in MS research.

We are at a time of animal bashing as there is not a model that has all elements of MS. That is true, but we have to remember that we can only model what you are told happens and here the pathology has much to answer. 

When I started my MS career it was written over and over again that MS was a disease of the white matter, but you just needed a pair of eyes to see that wasn't the case because you can see grey matter lesions with the naked eye.

Maybe the problem was the pathologists weren't doing the dissection, they maybe had technicians doing the work dissecting the brain, doing the sections and then staining with luxol fast blue, but because them pathologists siad there was no myelin in the grey matter the technicians would destain the sections until there was no stain in the grey matter and lesions missed. It was only when they started staining with antibdies that gey matter lesions were evident.
The imagers had missed this too because their machines could pick up lesions.

Then there is nerve loss issues...it has only become an issue when it was rediscovered in 1997/1998, but there was a long literature and agin using your eyes atrophy can be seen with the naked eye.

The problem is if you looked a group of pathologists in a room we would get the same answer of what are the pathological mechanisms occuring in MS.

What happens when you look weeks and months and years after the event. We know in EAE it looks very different. 

However the authors have a point because the models are driving ideas on potential therapies and there are powerful dogmas driving these choices. If the choices are based on false ideas then they are a based on a pack of cards....waiting to fall.

We are focusing on Th17 as a cause of MS....CD4 depletion has failed, blocking interleukin 17 has failed...(reducing lesion load by 50% is a failure). what's the evidence to support this in MS

What are the CD8 doing what makes them arrive. Surely the target must be in the CNS tissue they are attacking. If it is a virus it must be there...why have the not been found..have they been found as every cell has endogenous retro virus in its genome, in most cases live virus is not made.

Should we be depleting CD8 cells?.....would this be dangerous 
because CD8 cells have regulatory cells in their population

What are B cells doing, presenting antigen to T cells, what type of B cells are important? Depleting B cells can certainly work in MS

What is happening in areas distant from where the pathology is done, etc, etc etc. 

I've seen loads of reviews questioning animal work but essentially nothing questioning the pathology and the clinical work. It is bad for business because it is suggesting the neuros are fallible.

Baker D, Amor S.Experimental autoimmune encephalomyelitis is a good model of multiple sclerosis if used wisely. Mult Scler Relat Disord. 2014;3(5):555-64.

Baker D, Amor S. Mouse models of multiple sclerosis: lost in translation?Curr Pharm Des. 2015;21(18):2440-52

However ,we know this is true because we not finding enough useful treatments and as ProFG has said I think we have thrown away useful treatments. Not the stuff you want to hear, not the stuff that puts the academics in a good light.

I think that response to therapy tells us alot and there has to by clues in interogating this. 

Is it all EBV and an ant-virus response.

1 comment:

  1. I've read even on animal models and very interesting organoid, unfortunately animal models are still necessary.

    So I agree with MD that the problem doesn't seem to be in the study models, but in whom "draws, collects, interprets/concludes" research.

    What are the real interests behind who conducts the study?
    MS face essentially as a genetic disease or autoimmune T cells?
    Why not look sink that exists in the nerve tissue of MSers?
    As you MD well said if a virus it'll be there, so that could boost progressively independent of an autoimmune disease activity.

    If there's doubt regarding the issue of vitamin D, why they don't focus once and for all the issue and resolve to solve it?

    Burkitt, Achong, Epstein and Barr didn't give up the theory that EBV led, was the cause of Burkitt's lymphoma and other diseases, until prove that they were right.

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