Sunday, 5 February 2017

Education. How does Daclizumab Work?

The response to therapy may provide useful clues about what causes MS.  So maybe we should have a look. Its all T cells, but what happens with ocrelizumab

However, these is no consistency of what works and what does not work.

Daclizimab is moderately effective at controling MS, but may not instantly fall into the easy to understand explanation.

The T cell Explanation

Many People believe that MS is mediated by T cells

Daclizumab blocks the interleukin-2 receptor called CD25 (IL-2RA). The interleukin 2 (IL2) receptor alpha (IL2RA) and beta (IL2RB) chains, together with the common gamma chain (IL2RG), constitute the high-affinity IL2 receptor.

Interleukin 2 is a T cell growth factor that is used to make T cell divide. Block the CD25 and this will stop T cells dividing and stops them becoming activated. No activation of T cells no MS.
That's simple. T cell immunologists are happy

However, the explanation used to describe the efficacy is different

The Innate Immune Explanation

Because CD25 is blocked, interleukin 2 does not bind well to the high affinity receptor, but it can bind to the intermediate affinity interleukin 2 receptor (IL-2RB, IL-2RG) on Natural Killer cells. This makes Natural Killer cells proliferate

Natural Killer cells are part of the innate system and are good at killing cancers and infections, so is this why it works because NK cells are killing the MS-virus (EBV) infection. 

This is a favoured idea by ProfG to fit with his EBV hypothesis and the Charcot Project.

However, there are other explanations

The B cell Explanation

Whilst activated T cells express CD25, B cells also express CD25, notably in B memory cells (CD19+, CD27+) and with dacliziumab treatment not only are T cells depleted but B cells are depleted too. In the study below in the right hand set of graphs in the bottom left is the effect on B cell numbers and you can see it dropps by about a half, in studies not in MS the CD19 population is depleted between 50-75%. So is this the explanation how MS works?


However, one thing it suggests is not quite right is the 

T regulatory Cell Explanation

Based on many, many EAE studies, it is suggested that autoimmunity is controlled by T regulatory cells (Tregs). 

Get rid of them and autoimmunity should get worse, as is reported over and over again in EAE. 

However this is not true in the case of MS. The Treg also express CD25 (and Fox3P) and are depleted yet MS gets better in most people, so this mechanism suggested by the T cell immunologists does not hold water. 

Can this be ignored?

I suspect the answer for T cell EAEologists, the answer is YES!


However maybe autoimmunity is augmented rather than it affecting MS, it appears daclizumab induces autoimmune-related skin problems that can be severe in some people.


COI: None relevant

5 comments:

  1. So by activating the NK, which could be "killing" whatever is causing the MS,and greatly impairs B cells, the side effect of Dac would be autoimmunity to the skin, just as Alemtuzumab leads to thyroid autoimmunity.
    This is strange because if MS really is an autoimmune disease and in theory all autoimmune diseases would share "common, root" causes and consequences, why these two drugs instead of solving the self-immunity issue once and for all end up generating other autoimmunities?

    ReplyDelete
    Replies
    1. Yep.

      I am going to try an explain alemtuzumab autoimmunity and will attend to writing the posts once the B cell posts have finished

      Delete
  2. Thanks for finding time to write this post MD. Dac doesn't sound like it adds much to what we already have at only moderately effective and not without risk. Unlikely NICE will approve in UK anyway.

    ReplyDelete
    Replies
    1. once the price is right I suspect it will be approved

      Delete
    2. 'moderately effective and not without risk'

      sounds like most DMT's for most conditions. you could even say the same about paracetamol

      personally, i think it's a really decent option. Patients appear to do very well on it in my experience

      Delete

Please note that all comments are moderated and any personal or marketing-related submissions will not be shown.