Sunday, 17 September 2017

Looking at circulating cells...are we missing a trick.

Giovannoni G, Wiendl H, Turner B, Umans K, Mokliatchouk O, Castro-Borrero W, Greenberg SJ, McCroskery P, Giannattasio G. Circulating lymphocyte levels and relationship with infection status in patients with relapsing-remitting multiple sclerosis treated with daclizumab beta.Mult Scler. 2017 Sep 1:1352458517729464.

BACKGROUND:Reversible lymphocyte count reductions have occurred following daclizumab beta treatment for relapsing-remitting multiple sclerosis.
OBJECTIVE:To analyse total and differential lymphocyte levels and relationship with infection status.
METHODS:In DECIDE, blood samples were collected at 12-week intervals from daclizumab beta- ( n = 919) or intramuscular interferon beta-1a-treated ( n = 922) patients. Infections/serious infections were assessed proximate to grade 2/3 lymphopenia or low CD4+/CD8+ T-cell counts. Total safety population (TSP) data were additionally analysed from the entire clinical development programme ( n = 2236).
RESULTS:Over 96 weeks in DECIDE, mean absolute lymphocyte count (ALC), CD4+ and CD8+ T-cell counts decreased <10% (7.1% vs 1.6%, 9.7% vs 2.0%, 9.3% vs 5.9%: daclizumab beta vs interferon beta-1a, respectively); shifts to ALC below lower limit of normal occurred in 13% versus 15%, respectively. Grade 3 lymphopenia was uncommon (TSP: <1%) and transient. Lymphocyte changes generally occurred within 24 weeks after treatment initiation and were reversible within 12 weeks of discontinuation. In DECIDE, mean CD4+/CD8+ T-cell counts were similar regardless of infection status. TSP data were consistent with DECIDE.
CONCLUSION:When observed, ALC and CD4+/CD8+ T-cell count decreases in daclizumab beta-treated patients were generally mild-to-modest, reversible upon treatment discontinuation and not associated with increased risk of infections, including opportunistic infections.



                             B cells are not just one subtype


Some people think go off topic too much but. 

My post are directed at PwMS, because you need to understand the real world of science, However, I hold my hands up and say yes in some instances other people will be the recipients of my wisdom. 

Every blog post gets linked to a paper's altmetrics. Pharma read the blog, academics and MS health care professionals, read the blog. 

So I admit this post is directed as a plea to pharma. But I think some, not all of you, may find this of interest.

We also need to publicize our papers and this is what I'm doing as it is one of ProfG's. 

It aims to link infection to lymphocyte counts, and unfortunately when designing the study I suspect that opportunities have been missed. However, the DECIDE study was done years ago 

ProfG was never going to post on this paper, so I am doing him a favour to get his altmetrics up.

In this study, looking at the action of daclizumab, there is no major lymphopenia. This is not surprising because it takes out activated (T & B) cells, oh and increases NK cells, it leaves most cells intact.  
Neuroimmunologists, have taken hold of the MS-field and every thing has to revolve around TH17 and Tregs. However,daclizumab is one of the agents that challenges this view, because daclizumab depletes Tregs, yet MS gets better...go figure. 

How does this figure in the bigger picture?

I guess if you are a T cell immunologist, you just ignore it. 

So if you have a T cell view then you ask do T cell numbers correlate with infections and the answer is no. 

However, T cells are only half of the lymphocyte repertoire and B cells are ignored. I must admit, I ignored them too...as  a T cell-mouse. However, the B cell repertoire houses long-lived antibody forming cells and these are unlikely to be depleted, thus keeping our protection against infection.

However, B cells are important in our fight against infection and so we have missed a trick by not phenotyping the B cells properly.

Importantly we must realise that B cells are not one type (this it the educational message for all:-). 

In pharma graphs, we see  just the CD19+ B cells as a single entity, but CD4 & CD8 naive and memory T cells and regulatory T cells. We need to breakdown the B cell subsets, because this, I think holds the key. 

Does Daclizumab deplete memory B cells in MS? Maybe this links to efficacy.

Does Daclizumab deplete plasma cells in MS? Maybe this links to infection risk.

At the last ECTRIMS last year, Biogen did a wonderful study when they did extensive immunophenotyping of people treated with dimethyl  fumarate. It showed that DMF gets rid of CD8 T cells and also memory B cells and depletes T regs too. 

Hope they did this for daclizumab too or if not hopefully they will do this for this daclizumab

If you are pharma planning these phenotype studies...please phenotype the  Beeees. 

CoI None

13 comments:

  1. Re daclizumab depletes T regs, hope this doesn't spell bad news for people stopping dac when B cells bounce back?

    Re phenotyping B cells, as a humble laymouse and pwMS reading this blog I've noticed T cells are always profiled to the nth degree but B cells are lumped together as CD19. Why is this? After the memory B cell paper out there for anyone to read and success of anti CD20?

    Re dmf, for this little mouse n=1, four months of dmf has left me with next to no CD8 nearly two years on. Not to mention tlc still depleted by more than 50%. Remaining lymphocytes must be good at what they do as I never get infections (hope I'm not gonna regret writing that) and MS rapidly worsening too :(

    Re curators want to reign you in? Really? Please don't reign in too much MD, or we'll all get bored and give up ;)

    ReplyDelete
    Replies
    1. There will be very few B cells affected as CD25+ and when they go they go.

      Not sure we know much about transitioning off daclizumab.

      As for B cells still not much traction. We will see if our next paper has a hard time again but I believe the data gets stronger. Maybe I am blinkered, I think many of the my colleagues are.:-(.

      Hope you keep doing well with DMF and stay infection free.

      Delete
    2. "As for B cells still not much traction. We will see if our next paper has a hard time again but I believe the data gets stronger. Maybe I am blinkered, I think many of the my colleagues are.:-( "

      Once more in english please..Blinkered ? why are colleagues
      blikered ? Why did the old paper have a hard time ? B cell traction ?

      Delete
    3. Blinkered....The referees had blinkers on as their world view was only T cell driven and they can't see beyond this

      Why are they blinkered...I don't know I guess they cannot assimilate information :-(

      We had to add a load of T cell stuff to keep the referees happyish

      Most people do not accept the relevance of memory B cells.

      Delete
    4. No way! But I was so excited when I read your paper as it showed, by gathering together thousands of trial results from pwMS that if the memory B cell is reduced MS improves and if it increases MS gets worse! Not to mention all the years of failure with anti CD4 (or whatever it was) and success of anti CD20.

      Ok I'm only a pwMS, but I can read ;-)

      Delete
    5. Yes way....there are people who get their info from places like ECTRIMS so unless the medical liason people tell them other wise the world view stays the same.

      Then their is the establishment who want to keep the status quo...I best say no more.

      Then there are the self-centred me, me, me people....it is hard to believe that one reviewer wanted us to remove the idea that the drug was working by a B cell as too speculative, but at the same time making us add their papers about T cells....I suspect because they wanted to do it for themselves...no wonder there recent paper when it said we dont know anything about how drugs work...the student who read thought it rubbish.

      As profG says there are early adopters, laggards and neuros...OK I added the last bit:-)

      Delete
    6. As profG says there are early adopters, laggards and neuros...OK I added the last bit:-)

      Lolllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllll

      Delete
    7. "Most people do not accept the relevance of memory B cells."

      hmm..as you say in u.k...Gobsmacked

      Delete
  2. It makes sense that Multiple Sclerosis is more complicated than the 26 letters of the alphabet. B's 🐝or T's ✝️ or Z's πŸ• Are too simple. Keep looking. Do drugs that help, like THC/CBD, act on helping your body differentiate between good and bad, helps draw away the bad and Lymphatic fluids of inflammatory process-scars. Does Biotin help? I understand if you don't allow my random sounding thoughts. I think it's good to look at what helps. Even if that begins as my observations as an old disabled nurse. Best Wishes on your journey to find the answers.meg

    ReplyDelete
  3. DearMeg the problem with THC is that you can't dissociate the good from the bad because the same receptor in different areas of the brain.

    However, antecdote can lead to scientific evidence.That is how sativex was developed

    ReplyDelete
  4. Why would MS researchers be doing a blog ???????????????????? for what reasons ?????????????????????

    ReplyDelete
    Replies
    1. World Peace:-)

      I know why I do it, you tell me why we shouldn't

      Delete
    2. This blog gives vital information to all those who have multiple sclerosis and really need help to make informed decisions about drug treatments etc. I value it tremendously as I only had a brief 20 minutes appointment the last time I saw my neurologist - poor chap was quite obviously under a lot of pressure and rushing to fit in all his patients.

      Delete

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