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