May 2020; 7 (3) ARTICLEOPEN ACCESS
Glatiramer acetate immune modulates B-cell antigen presentation in treatment of MS Darius Häusler, Zivar Hajiyeva, Jan W. Traub, Scott S. Zamvil, Patrice H. Lalive, Wolfgang Brück, Martin S. WeberFirst published March 17, 2020, DOI: https://doi.org/10.1212/NXI.0000000000000698
You can not have it both ways. In the European Medicines Agency blurb it has said that glatiramer acetate (GA.Copaxone) is believed to target the mechanism thought to be responsible for the pathogenesis of MS.
Therefore as the mechansims thought to be responsible for MS, has changed over time, so has the mechanism of action of GA.
However one detail has escaped the many, many, many GA studies and this is……………the fact that GA does not appear to be a highly active disease modifying drug. Therefore it says that by what ever the mechanism it works, if must not be that effective. Because if it has dramatic impact on an essential mechanism then the efficacy has to be higher. You can’t have it both ways.
I have suggested that an effect on memory B cells is important to show efficacy. There is the hypothesis. So what is seen?
Now do people think?…or just put out a mechanism….In this study it is reported that MHC class II is upregulated and we knwo this is involved in presenting protein fragments to CD4 T cellsor and interleukin 10 increases so its immunoregulation. So next we can do the experiment in mice and it upregulated MHC class II in the mouse, so now let’s see what happens in EAE.
It increases antigen presentation…which is rather odd when we are told that the potent B cell inhibitors work because they decrease antigen presentation.
However, as we know GA is magic because it can increase antigen presentation not to activate T cells but to …….you guessed it…to induce the standard mechanistic chestnut……yep to make T regulatory cells….the scurge mechanism of mouse EAE. There you have it Glaterimer acetate makes T regulatory cells…QED.
Now remember you cannot have it both ways. Lets look what it did to EAE and as you can see the results are actually rather rubbish, so does this mean that T regulatory cells are also rubbish at controlling immune responses, as you can’t have it both ways.
So a doubling of T regulatory cells essential does nothing to EAE, if you can kid yourself that this is relevant to MS but you have to recognise that the animals essentially all get sick…so the mouse data if translated into human studies would say that daily subcutaneous GA will not work in MS.
You dont’ get half a relapse after all. Now we know there is a significant effect with glateriamer acetate in relapsing MS but is it a highly effective agent..remember you can’t have it both ways.
P.S. I have to say I am not that convinced that you can use these models to tell us much about the role of B cells in MS, as Mouse EAE responds to anti-CD20 about as well as it does to subcutaneous glatiramer acetate.