Saturday, 13 May 2017

DMF kills Memory B cells

Smith MD, Martin KA, Calabresi PA, Bhargava P.Dimethyl fumarate alters B-cell memory and cytokine production in MS patients. Ann Clin Transl Neurol. 2017 Apr 17;4(5):351-355.

We evaluated the effect of dimethyl fumarate (DMF) treatment on B-cell memory and cytokine production in 18 patients with relapsing remitting multiple sclerosis (RRMS) using peripheral blood mononuclear cells obtained prior to and at 6 months post-DMF initiation. We noted a decline in the absolute B-cell number with DMF treatment, with a preferential depletion of memory B cells and a concurrent increase in naïve B cells. We noted significant reductions in GM-CSF, TNF-α, and IL-6 producing B cells with DMF treatment. These effects on the B-cell compartment may underlie the beneficial effects of DMF in RRMS.

Looks like we have hit on "flavour of the year" and I'm not sure how to deal with conforming to the norm:-(. This is that the agents that seem to be affecting MS the most are the memory B cells. 

I'm sure you are getting bored with this endless stream of supportive data. However are the T cellers interested?...Probably not.

However I have said it is the absolute number that is important , if the memory cell population within the CD19 population does down, the other CD19 populations go up as a percentage. But if you rely on percentages you can look a real idiot when you realise the absolute number of cells tells you something else. But based on what we published, perhaps the data in this paper says why you can do better with DMF.

So have a read of our paper and look at figure 4.

This cost me a few hundred quid to pay for the copyright, but I did this so that you don't have to look through a few papers. 

What you can see is the highly active agents keep the memory cells as a low percentage of the CD19 positive population. But let's look at the results from this current paper (above) and you can see  what may the issue. For the highly active agents, they deplete memory B cells below 20% of the CD19%  population. 

You can see that a few people treated with DMF don't make that mark. 

Is this a reason for failure? As you can see, I am pressing a few buttons so that the companies with the data will prove me wrong. 

4 comments:

  1. Do memory B-cells in peripheral circulation transform one day into EBV driven memory T-cells in the brain follicles? How does DMF work at stopping progression-ie. mitochondrial support-Nrf-2 inhibitor or possibly deplete incoming EBV memory B-cells from periphery? Why did Biogen abort their trials with DMF in progressive patients when they claim in their short trials to halt progression in RRMS around 38% I believe? Biogen not proceeding with trials seems extraordinarily questionable given the lack of any meaningful treatment in progressive MS. If DMF lowers CD8 T-cellcount, would this not theoretically worsen MS as CD8 cells are supposed to control or destroy EBV driven memory B-cells? Sorry for all questions MD and if you answer much appreciated (if you don't you are still appreciated).

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  2. Memory B cells do not transform into EBV driven T cells, but if EBV infects B cells it can make them immortal. Is there evidence that DMF stops progression. It seems that is the marketing myth created, but not sure there is proof.
    Alot was spun around Nrf-2 but this may not be the working mechanism in RRMS.
    There does appear to be a depletion over time of the CD8 population and you could say if CD8 were killing EBV B cells as a problem, then shouldn't MS get worse. It doesn't and so may the CD8 idea is wrong. However, DMFis also killing the memory B cells and so maybe this ofsets the destruction of the CD8 T cells. However it could mean a whole in the anti-viral repertioire.

    Now to your other question about studies with DMF, I suspect there may be no more. This could occur, because court cases have been lost and most of the profit will go as on royalties that have to be paid to a patent Troll.

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  3. Sorry, I meant do peripheral memory B-cells eventually transform into EBV-driven B-cells in the brain that eventually form the EBV-controlled B-cell lymphoid follicles in the brain? Does EBV infect and control the memory B-cells in the periphery or the brain?

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