The message is not getting heard, fingolimod works by inhibiting T cells. It’s behind you!!!

T

Pre-treatment T-cell subsets associate with fingolimod treatment responsiveness in multiple sclerosis. Ghadiri M, Rezk A, Li R, Evans A, Giacomini PS, Barnett MH, Antel J, Bar-Or A.Sci Rep. 2020 Jan 15;10(1):356

Biomarkers predicting fingolimod (FTY) treatment response in relapsing-remitting multiple sclerosis (RRMS) are lacking. Here, we performed extensive functional immunophenotyping using multiparametric flow cytometry to examine peripheral immune changes under FTY treatment and explore biomarkers of FTY treatment response. From among 135 RRMS patients who initiated FTY in a 2-year multicentre observational study, 36 were classified as ‘Active’ or ‘Stable’ based on clinical and/or radiological activity on-treatment. Flow cytometric analysis of immune cell subsets was performed on pre- and on-treatment peripheral blood mononuclear cells (PBMC) samples. Decreased absolute counts of B cells and most T-cell subsets were seen on-treatment. Senescent CD8 + T cells, CD56 + T cells, CD56dim natural killer cells, monocytes and dendritic cells were not reduced in number and hence relatively increased in frequency on-treatment. An unbiased traditional manual analysis of T-cell subsets suggested a higher pre-treatment frequency of CD4 + central memory T cells (TCM) in patients who were subsequently Active versus Stable on-treatment. Lower pre-treatment terminally differentiated effector memory (TEMRA) cell frequencies were also seen in the subsequently Active cohort. Together, our data highlight differential effects of FTY on peripheral immune cell subsets and suggest that pre-treatment T-cell subset frequencies may have value in predicting FTY treatment response.

So looking at the summary it argues against the hypothesis that we have suggested that agents that are active in MS all target memory B cells. Therefore, I need to explain this one or maybe I need to change my views. It is open access so you can have a view. On first glance it seems the hypothesis is challenged, or is it? Is it really?

This week I had a look at methotrexate and it was not that great at depleting memory B cells and guess what? In a head to head with interferon it was worse than beta interferon in RRMS. Hypothesis not disproved, carry-on. Science should be about disproving ideas not doing everything to confirm what you think you know. This seems to be the approach here.

However, it sounds like the authors who have spent alot of their time studying B cells, lack of focus, as they imply here that fingolimod is working by effects on T cells. It depletes them all, even the effector memory population that are reported not to be relatively unaffected by sphinogosine 1 phosphate modulation. If a B cell guru flip flops with last week B cells, this week T cells, no wonder the general public is confused and dosen’t know where to look. But it keeps happy families and it is all a balance, as long as its T cells are the most important cells 🙂

In true Pantomime spirit let’s should out “it’s behind you”, because you may be not looking in the right place. Maybe the authors are right and it is all down to T cells, but you have to look at alternatives and dismiss them.

Scientific reports is the alternative to PLOS ONE and is not reviewed on the basis of the result but the soundness of the methodology. However, I have to bang my head against a wall here as the study goes to great lengths to study T cells subsets and here in 2020, we are still viewing B cells as a single cell type. We are missing vital information, meaning the study actually is fundementlly flawed. OK the study would have been planned before this thought but hey, Prof Bar-Or was doing B cell stuff from 2008 and you would think knew the B cell population was not one cell type.

However how do you disprove a hypothesis is you don’t look and there is no mention of B cell subsets and so I have to say I think this study is methodolically flawed. Maybe there is paper two in the wings because looking at the antibody panel used for staining, data from some but not all of the relatvent B cell subsets could have been detected. They could get at total memory B cells and plasmablasts, but they did not even get a mention.

Do a paper on T cells without really mentioning B cells and no body cares. Do a paper on B cells without mentioning T cells and the referees usually soil-themselves and make you add a section on T cells and T regulatory cells. This study is a massive amount of work using new technology but to me is a job half-done. Ask how fingolimod works and we trot out the old it holds cells in the lymph node chestnut, ut is it really that simple?

So when Novartis sponsors a study to do the same with siponimod take a more unbiased look and check out the B cells you may get a pleasant surprise.

COI multiple but not really relevant

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