Tuesday, 28 October 2014

To deplete or not to deplete that is the question?

Leucopaenia (low white blood cell) has become a hot topic of the past week, with the realisation that people who get leucopaenia (low white blood cell counts) are more at risk from infection and the dreaded PML. 

So now there  is a rush to stop the level of lymphopaenia from occurring, but one question is. Do we want our cake and eat it?Because we have to ask how do the MS-drugs stop MS?  

In many cases it is because of leucopaenia. This may be physical depletion of cells out of the body and the blood, in particular, such as with alemtuzumab or rituximab or it may be a functional leucopaenia, such as with Tysabri, where the cells are in the blood but because they cant get out of the blood they are powerless to deal with the infection within the brain.

I have heard it said that the efficacy of alemtuzumab or cladribine does not relate to the level of leucopaenia, which may be in part the case, but if you did not get leucopaenia would these drugs work...I really doubt it. 

They are integral to the mechanism of action, you need it to stop disease however if you maintain it, leucopenia will eventually lead to problems of immunosuppression which is the generation of infection and cancers....This is simple biology and we should not forget this you do not get one without the other if you maintain the treatment.
CD4 depletion was tried in MS and failed in MS. Does this mean that MS is not caused by the action of T cells? This is interesting when in animals CD4 T cell depletion inhibits about every known autoimmune disease, even if they are T or B cell autoimmunities?

CD4 treatment in humans was tried when AIDS was looming its ugly head and the Neuros were scarred that if you depleted the CD4 T cell number to low then you might get AIDS and so they only depleted about 50%. 

Yet the animal studies were based on an 80-90% depletion and depletion of  50% in animals would not be good enough to stop autoimmunity in animals, so why on earth would it work in humans? In my humble opinion the trial was doomed before it was even started!

This is not translation but throwing away good biology!

However, in animals we can say that depletion is absolutely required for action and the depletion within a few days of giving antibody is about 95% but within a few weeks it is about 60% so if you do a blood sample months after treatment as is the norm in human studies you do not get a picture of what has happened previously....maybe relating to the statements that leucopenia are not related to the mechanism of action, when it clearly is.

In contrast to the 60% depletion of anti-CD4  antibody, Alemtuzumab knocks T cells down by over 90% and inhibits relapsing MS. So the people are T cell lymphopaenic but if you look in the blood then the white cell population is filled with B cells within a few months, so they are not leucopenic on a total white cell count when they are if fact leucopaenic for certain cell types.

It is probable that PML involves loss of CD8 anti-viral responses as well as other immune arms. 

But now back to the T cells. Are they not involved in MS?...if they are not, hundreds of people are wasting their time, including the EAEers (No snarky comments please!). 

However it looks like the effective treatments in MS cause depletion of B cells like anti-CD20.....The doubting immunologists state that this is because anti CD20 takes out a subset of T cells and they are the problem. 

This makes the point that you have to know what is interesting when you define leucopaenia. Just counting cell numbers may be meaning less. If it is those few T cells that are critical and their loss makes no difference on leucopaenia.

With Alemtuzumab there are massive reductions in T cells in including T reg cells, is this why autoimmunity comes back? Well the T reg to T cell ratio may favour more T regs but the T reg to B cell numbers are dwarfed. At ACTRIMS2014 it was shown that CD19, CD5+ B cells massively proliferate after Alemtuzumab....Is this why you get B cell autoimmunities? In contrast the CD19+, CD27+ memory B cells were flatlined...is this why MS is halted? 

I don't know but the point I am making is that the you need to know what you are looking for when you are talking about leucopaenia to know if it is functionally relevant or not. Without that ,looking for a  blanket leucopenia may be not sufficiently meaningful.

4 comments:

  1. Anti-CD20 treatment is working very well and a complete blood count is done a few times a year.

    All the leucocyte levels have always been in the normal range. Lymphocytes are sometimes close to the lower end of the normal range

    The Immunoglulin IgG level is sometimes a little below the normal range

    I hope this means I don't need to worry about PML

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  2. Dear MD,

    Thanks for this information.
    Would it be possible to put it in a table DMT x the Leucocyte(s) they reduce?

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    Replies
    1. Dr M & M has done something like this and has written a paper

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