Friday, 24 March 2017

More on B cells.We don't all have the same ideas. Who is right?

We don't normally report on reviews. But we have a couple of recent ones

Nguyen AL, Gresle M, Marshall T, Butzkueven H, Field J. "Monoclonal antibodies in the treatment of MS: emergence of B-cell targeted therapies". Br J Pharmacol. 2017 Mar 20. doi: 10.1111/bph.13780. [Epub ahead of print]

Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS, and one of the most common causes of disability in young adults. Over the last decade, new disease modifying therapies have rapidly emerged, including monoclonal antibodies (mAbs) that have provided highly targeted therapies with superior efficacy compared to platform therapies. In particular, monoclonal antibodies directed against CD20-positive B cells have shown remarkable results in recent clinical trials, and renewed interest in the mechanism of B-cell depleting therapies to ameliorate relapse activity and progression in MS. In this manuscript, we will review the mechanisms of action and clinical evidence of approved and emerging mAbs, with a focus on B-cell targeted therapies


We did the same but came to very different conclusion.
Here it is all to do with B cell regulatory function rather 
than B memory function.

If you work in percentages if one goes down (Memory B cell subsets) the others (Regulatory B cells) must go up.

However in some cases because we have tried to work with absolute numbers we know that B memory cells go down

We have recently published 
our first part of the original series of papers written 
just before Christmas.
The last part of the originally submitted studies 
actually surfaced first

Baker D, Marta M, Pryce G, Giovannoni G, Schmierer K.
EBioMedicine. 2017 Feb;16:41-50. doi: 10.1016/j.ebiom.2017.01.042

This has gained some Interest on the Blog as it becomes evident that this subset of Bcells is infected by Epstein Barr Virus.

Maybe there are alternative explanations to the view that B cells help T cells do it all.


Following dogma can lead us down a garden path, as we will see as the next part of the equation eventually surfaces.

However, this thought does not even occur on some people's radar
So here is a standard view

Ocrelizumab in multiple sclerosis: markers and mechanisms.
Hohlfeld R, Meinl E. Lancet Neurol. 2017;16(4):259-261.

They say

"Anti-CD20 therapy acutely depletes CD20+ cells in the periphery, but only causes a delayed and modest decline of circulating antibodies.CSF studies with rituximab revealed decreased T-cell and B-cell counts, whereas intrathecal IgG production was relatively spared. For these reasons, depletion of pathogenic antibodies might not be the dominant mechanism of action of ocrelizumab in multiple sclerosis, although this cannot be totally excluded". 


"Overall, it seems plausible that anti-CD20 therapy partly acts by eliminating the potent antigen-presenting function of B cells, a view supported by animal experiments. Furthermore, B cells produce many pro-inflammatory and anti-inflammatory cytokines. Profound B-cell depletion might therefore lead to changes in the cytokine network, dampening pathogenic T-cell responses and thereby contributing to the beneficial effect of anti-CD20 therapy in multiple sclerosis".

"Lastly, it should be noted that anti-CD20 therapy is not entirely specific for B cells, as it also depletes CD20+ T cells, which are about 5% of blood T cells".

Whilst our review accommodates all these views, it gives an opinion and then it puts the focus in a very different direction. As memory B cells are not really mentioned. However, again we see that animal studies again tell us how MS drugs work. 

Although I am aware that the animal studies support such a mechanism, I personally think the data from treatment of animals with anti-CD20 is weak. 

Should we do a critique of the animal data? 

If the animal data is on shaky ground, where does it leave the hypothesis?



7 comments:

  1. How does this fit in with the latest paper by M Pender et all, 2017?

    ReplyDelete
  2. I know mice are nice, but I would prefer real life data from treatment with anti CD20 in people who got rituximab/ocrelizumab.

    As for the antibodies not going down on anti CD 20 therapies... they tend to go down somewhat after many treatment cycles and in some people we actually had to reduce dose/stop rituximab because ... it was getting a bit unpleasant, especially if the patients were getting infections.

    ReplyDelete
    Replies
    1. Yep, as MD keeps saying, EAE is not MS it's a mouse model (and sounds like one with lots of holes in it too - do mice like Leerdammer?)
      You're in a privileged position CD20 to be able to witness the effects of rituximab in real people. Interesting what you're seeing bearing in mind comments from Barts team re frequency of dosing.

      Delete
    2. Judy, but it is not MS I am looking at ...

      Delete
    3. True, but it's still ai disease in real people....

      Delete
  3. Could you write with left-aligned text throughout? Much easier to read.

    ReplyDelete
  4. Here is the reference:
    Defective T-cell control of Epstein-Barr virus infection in multiple sclerosis.
    Pender MP, Csurhes PA, Burrows JM, Burrows SR.
    Clin Transl Immunology. 2017 Jan 20;6(1):e126. doi: 10.1038/cti.2016.87.

    ReplyDelete

Please note that all comments are moderated and any personal or marketing-related submissions will not be shown.