Thursday, 13 April 2017

What Does B cell depletion do in Animals

#MSresearch B cells role in EAE more wishful thinking

This is a repost but you get access to paper now

Eseberuo Sefia, Gareth Pryce, Ute-Christiane Meier, Gavin Giovannoni, David Baker Depletion of CD20 B cells fails to inhibit relapsing mouse experimental autoimmune encephalomyelitis. Mult scleros is and related disorders DOI: http://dx.doi.org/10.1016/j.msard.2017.03.013

Background. Multiple sclerosis (MS) is often considered to be a CD4, T cell-mediated disease. This is largely based on the capacity of CD4 T cells to induce relapsing experimental autoimmune encephalomyelitis (EAE) in rodents. However, CD4-depletion using a monoclonal antibody was considered unsuccessful and relapsing MS responds well to B cell depletion via CD20 B cell depleting antibodies. The influence of CD20 B cell depletion in relapsing EAE was assessed.
Methods. Relapsing EAE was induced in Biozzi ABH mice. These were treated with CD20-specific (18B12) antibody and the influence on CD45RA-B220 B cell depletion and clinical course was analysed.
Results. Relapsing EAE in Biozzi ABH failed to respond to the marked B cell depletion induced with a CD20-specific antibody. In contrast to CD20 and CD8-specific antibodies, CD4 T cell depletion inhibited EAE.
Conclusion. Spinal cord antigen-induced disease in ABH mice is CD4 T cell-dependent. The lack of influence of CD20 B cell depletion in relapsing EAE, coupled with the relatively marginal and inconsistent results obtained in other mouse studies, suggests that rodents may have limited value in understanding the mechanism occurring following CD20 B cell depletion in humans



UNTIL 25 MAY 2017 YOU CAN CLICK ON THE LINK BELOW  FOR FREE ACCESS 

https://authors.elsevier.com/a/1UqUO7skoetmZ4



If is perhaps apt that this paper has surfaced this week, just as Ocrelizumab gets a licence in the USA. 

This will mean a flurry of activity to do more work to sort out disease mechanisms targeted, so a load more transgenic mice will be made and used.

Should we say Schtop!

We recently reported on a review on B cells in MS.
https://multiple-sclerosis-research.blogspot.com/2017/03/more-on-b-cellswe-dont-all-have-same.html

They went through the mechanisms of how CD20 depleting antibodies work.

1. They dismissed a roll for antibodies as CD20 does not quickly deplete antibodies, because it does not deplete plasma cells

2. They didn't even think of the viral reservoir idea.

3. They said that they worked on antigen presentation, 
    because that is what the animals studied showed.

I said "If the animal results are based on dogey-ground, 
Where does it leave the hypothesis?" 

So hot off the press...Here we go.

What did anti-CD20 do in the beasties?

Major depletion of B cells, but that is where the good data ends.

What does it do Relapsing EAE? 
In our hands........Nada...Nyet...Nothing!

However, deplete CD4 T cells and disease is gone!

So how do you report this?

I thought we could put it in the context of other studies

So what have other people found? 

It made us look at the data 

So rather than write about it, where it would go in one ear and out the next.

I thought it was easier to pay for the copyright fees to get permission to reproduce the figures in the paper, so you can all see for yourself.

I showed DrK the figure below, before he knew what the content was and he said "What ever it is, it doesn't look very good"

What's your take?



(A) Shows depending on when start treatment to induce CD20 B cell depletion it can either: 
  • Augment
  • Do Nothing
  • Inhibit Disease

But let’s face it. It’s only a partial inhibit, not a wipe out like fingolimod or CD52 antibody could do.

(C) Shows so called B cell-dependent EAE where anti-CD20 works, there is a non-B dependent EAE induced with peptide that doesn't work. 

However, I thought “Hang on. That's the same EAE used in A & C were the antibody is working, so is it B cell independent?

In addition if you treat before disease induction it's worse in (A), but better in (B) and (C). So not consistent.

But really as DrK says. The effect in (A) & (C) are rather rubbish.

So the effect in (B) saves the day...yeah it flat lines disease.

But look at the graph at the bottom of (B) on the left. It says B cells were depleted out or sight. But in (B) on right CD4 T cells were also depleted out of sight, so if you deplete T cells with anti-CD20.....it works in animals. So the answer is that the results says that rodent EAE is a T cell mediated disease.

I have no issues with that, but as we have been saying it looks like T cell depletion isn’t that effective in MS.

So no major T cell Depletion with the anti-CD20 antibody we used and there was no effect on EAE.

So if it is antigen-presentation?
Shouldn't the B cell depletion do better if it was?

Are you still an antigen-presenting B cell fan?

Yes it happens.
But, is this how anti-CD20 works in MS?

Maybe Mice can't give us the answer. 
Maybe we should also say marmoset EAE failed to predict the effect of BAFF/APRIL 
Maybe the answer can only be found by studying humans

CoI: This is work from TeamG

7 comments:

  1. No offence, Mouse Doctor, but mice have mislead us ... not the first time either.
    That said, nobody will let us inject new things into humans first :-)

    ReplyDelete
    Replies
    1. Not the mice...the people in charge of the mice:-)

      Mice are not all bad
      Rituximab...ocrelizumab made in mice

      Delete
    2. OK, OK, mice good, humans less so... Happy now? ;-)
      But it is funny how different their immune system seems to be.

      Delete
    3. Their selective enviroments are different. Mice have evolved to eat rabbish and live in dirty holes and can tolerate stuff that we dont.

      Delete
    4. Looks like you're out of a job MD!
      And no changing your name to Marmoset Doctor, hard to believe that's even legal?

      Do any other primates get MS? Not that it's any help with research, just wondered. Not sure how it would be noticed in a chimpanzee ;-)

      Delete
    5. Do any primates get MS....Yes...these primates are called humans

      Do any non-human primates get MS...No...they get EAE.

      However, there is a colony of japenese macaques in portland oregon that get a demyelinating disease. This is caused by a herpes virus like EBV.

      Out of a job..yes its coming and posts like this will hasten my demise:-(

      Marmoset Doctor...No chance.

      However, we sort of gave up on mouse EAE, immune studies about ten years ago, but there are issues like symptoms and progressive disease that we still have some mileage.

      However we do dabble with the immune stuff and like this we get answers that dont fit with dogma. So now to cause mayhem with human immunology...

      Delete
  2. https://en.wikipedia.org/wiki/Hygiene_hypothesis

    "Strachan's original formulation of the hygiene hypothesis also centred around the idea that smaller families provided insufficient microbial exposure partly because of less person-to-person spread of infections, but also because of "improved household amenities and higher standards of personal cleanliness".[2] It seems likely that this was the reason he named it the "hygiene hypothesis". Although the "hygiene revolution" of the nineteenth and twentieth centuries may have been a major factor, it now seems more likely that, although public health measures such as sanitation, potable water and garbage collection were instrumental in reducing our exposure to cholera, typhoid and so on, they also deprived us of our exposure to the "old friends" that occupy the same environmental habitats.[8][9]"

    ReplyDelete

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