Thursday, 2 March 2017

B cells for MS, what evidence smashes the idea?

We asked you (steve S is very quiet and so is Mr T!) to see if you can find papers that mash the idea that B cells are the beasts that drive MS.

Sadly not much traffic on this one. 

So maybe we are not talking nonsense or maybe you can't be bothered:-( 

However, we have had a challenger.

As I have said we can walk through these and maybe Mr Karl Pooper will be right and we will disprove the hypothesis and we will move on
Who is Karl Popper have a listen (click here)

Although we had said that there is not a 10-20% depletion of T cells because about 10-20% of T cells express low levels of CD20

Palanichamy A, Jahn S, Nickles D, Derstine M, Abounasr A, Hauser SL, Baranzini SE, Leppert D, von B├╝dingen HC.Rituximab efficiently depletes increased CD20-expressing T cells in multiple sclerosis patients. J Immunol. 2014;193(2):580-6.
We didn't think that was enough as CD4 depleting antibodies had failed in MS and had depleted more than this

However, a referee who was quite smug and said that following rituximab 

There is actually 55% T cell depletion by rituximab (Cross et al. 2006) and this is why anti-CD20 works because it is killing T cells.

Cross AH, Stark JL, Lauber J, Ramsbottom MJ, Lyons JA. Rituximab reduces B cells and T cells in cerebrospinal fluid of multiple sclerosis patients. J Neuroimmunol. 2006; 180:63-70.




Holy c**p has the bubble burst already, You can see for yourself T cells down from 600 and a bit down to 300 T cells in the CSF.

So how do we counter old smuggola?

First thing first read the paper, not someone's interpretation of the paper.

So now the abstract

Effects of B cell depletion by rituximab, a monoclonal antibody to CD20, were studied in patients with relapsing MS that had not responded optimally to standard immunomodulatory therapies. Flow cytometry demonstrated reduced cerebrospinal fluid (CSF) B cells and T cells in most patients at 6 months post-treatment. ELISAs demonstrated modest reductions in serum antibodies to myelin oligodendrocyte glycoprotein and myelin basic protein in some subjects. Beta-interferon neutralizing antibodies were reduced in three subjects, but developed anew after treatment in three others, suggesting caution in considering rituximab as a means to eliminate NABs. In summary, rituximab depleted B cells from CSF at 24 weeks after initial treatment, and this B cell depletion was associated with a reduction in CSF T cells as well.

There you see it, rituximab is dropping T cells and this is the headline 

But look. This is at 6 months after the injection of rituximab!
What can we say?
  • Depletion of T cells, by CD4-depleting antibodies, by about 70% was not enough to stop MS. So is 55% depletion enough.
  • Our Animal studies say No.
  • If you inject rituximab into the cerebrospinal fluid it does not remove B cells from the CSF, it leaks out and kills cells in the blood, so shortly after injection into the blood rituximab isn't killing B cells in the CSF, but 6 months later they are gone (see picture above)
  • If you inject rituximab in the blood it depletes B cells from the blood and importantly stops attacks in MS for at least 6 months.
  • In 6 months this is ample time for inflammation which is under control due to the rituximab to subside and what would we expect if inflammation is inhibited.
  • Yep..less B cells and less T cells in the brain and what do we find 6 months after rituximab....less T cells and less B cells in the brain.
I say keep trying! .....Four
Next! 

Editorial: Lymphocytes in MS and EAE: More Than Just a CD4+ World.Rangachari M, Kerfoot SM, Arbour N, Alvarez JI.
Front Immunol. 2017 Feb;8:133.


20 comments:

  1. I am not an immunologist, but the religion-like divisions between the T-cell people and the B-cell people seem every bit ridiculous from my point of view :-). You need B and T-cells to mount an immune response and you will see changes in both cell populations if the treatment is effective.

    ReplyDelete
    Replies
    1. Ah but dogma can be the enemy of progress. If we could identify the population of cells directly resposible, these could be specifically targeted whilst leaving the rest of the immune system essentially intact. That's why we bang on about it and if the B cell theory is correct it may provide more evidence for the central importance of EBV as some form of trigger in these cells.

      Delete
    2. Not sure the B cell people have the the religion, but if you question the T cell activity then you see disbelieve.

      Delete
    3. For EAE you actually dont need the B cells.

      Delete
    4. Well, isn't that the main problem with this EAE model?

      Delete
    5. It could be given what we're finding out with regard to MS but let's not throw the baby out with the bathwater!

      Delete
    6. @MD2 suppose it is the memory B cells you want to get rid of. How do you go about it? There is no way of knowing what they are reacting to and getting rid of the bad lot. You would have to indiscriminately kill all of them, which is I suppose what HSCT does - like wiping the immunologic memory slate clean and starting from the beginning.
      But say it is the EBV that was causing the problem. This thing is everywhere, within a few years you would have met it again.Then what, another wipe? and then another?

      Delete
    7. MD, just another silly question... what happens after HSCT, is a person who was EBV postitive turning negative post HSCT? If so, if the MS returns post HSCT only in folks who are EBV positive again, wouldn't that support your theory of EBV in MS?

      Delete
    8. Not a silly question a good one I would say...what do the papers say

      Delete
    9. Suppose it is the memory B cells you want to get rid of. How do you go about it?

      There are many ways of doing this, but to say them would stop us or other people getting patents on them. You can refine what to get rid of based on publications of papers out there.

      If you are profG he would argue the solution is getting rid of the viruses in B cells.

      Delete
    10. If memory B-cells, harboring some latent virus - perhaps EBV, are the culprit then the failed anti-viral trials such as Charcot have pointed to latent EBV. This DNA needs to be excised using genetic engineering similar to other genetic diseases. That is of course assuming EBV DNA expression is to blame.

      Delete
    11. AnonymousThursday, March 02, 2017 5:46:00 pm - non myelo hsct doesn't kill all b cells, though it does kill many.

      it depends on agents used and amounts etc, in part. in part i suspect it also depends on ind. person

      Delete
  2. "Not a silly question a good one I would say...what do the papers say"
    People after HSCT have to be vaccinated again ... so the humoral memory goes south with HSCT ... but it may vary on how tough the protocol is.
    On rituximab it does not go to nothing, we do vaccinate people before starting rituximab, so on its own it is not as good a wipe-out - if you know what I mean:-).

    ReplyDelete
    Replies
    1. only people with ablative HSCT need vaccinating , non ab;lative dont

      Delete
    2. What about NK cells rising as a measure of drug effect in MS?

      Delete
    3. only daclizumab increases NK cells, maybe small rise of CD56bright subset with alemtuzumab but others decrease CD56 levels

      Delete
    4. Well, I think the others do it too. Rituximab, for example. Ocrelizumab is similar, would do the same, presumably. And even Copaxone is trying to hang on the NK train.

      Delete
    5. :-) copaxone what doesnt it do?
      NK cells are used by CD20 cd52 antibodies to do the killing.

      Delete
    6. MouseDoctorFriday, March 03, 2017 10:56:00 pm
      only people with ablative HSCT need vaccinating , non ab;lative dont

      some people with non myelo need vaccinating too...

      Delete
  3. although what is done in the clinic is not always 100% hard science. MD might like this one:
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4360192/

    ReplyDelete

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