Sunday, 15 July 2018

How do CD20-depleting antibodies work..To T or Not to T that is the Question.

As soon as rituximab and then ocrelizumab, which are both CD20 depleting antibodies, were shown to influence relapsing MS, implicating B cells as a target for MS.

We had a flow of papers indicating that T cells express weak amounts of CD20. This view is trotted out time and time again, if you mention B cells as an issue.

These T cells are depleted by rituximab and so the T cell biologists have clung to the idea that rituximab works by depleting T cells.

Palanichamy A, Jahn S, Nickles D, Derstine M, Abounasr A, Hauser SL, Baranzini SE, Leppert D, von Büdingen HC. Rituximab efficiently depletes increased CD20-expressing T cells in multiple sclerosis patients. J Immunol. 2014;193:580-586.

Is this a desperate view to cling to? 

I think so

(A) The Tcellers are happy to accept that depleting 5% of T cells (i.e. the CD20+ T cell subsets) inhibits MS, whilst dismissing the fact that 70% depletion of (CD4) has minimal effect. This makes minimal sense to me

(B) However, it is not only CD20 that implicates activity on B cells. 

Do T cells express Bruton Tyrosine Kinase and CD19, because these B cell depleting agents also work in relapsing MS.

The answer is here.

Schuh E, Berer K, Mulazzani M, Feil K, Meinl I, Lahm H, Krane M, Lange R, Pfannes K, Subklewe M, Gürkov R, Bradl M, Hohlfeld R, Kümpfel T, Meinl E, Krumbholz M. Features of Human CD3+CD20+ T Cells. J Immunol. 2016;197:1111-7. 


"These cells display a lower level of CD20 than B cells and lack markers typically found on B cells such as HLA-DR, CD40 and CD19".

"We sorted CD3+CD20+ cells, CD3+CD20 T cells, and CD19+CD20+ B cells from healthy donors to compare their transcript levels of CD3, CD19, and CD20 by quantitative PCR"......they got


Yep the same result, the CD20+ T cells are not going to be hit by CD19-depleting antibodies.

So can the effect of CD19 depleting antibodies be explained via a T cell mechanism?

Maybe its time to think that really CD20 works, because its depleting B cells.

10 comments:

  1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4485721/

    CD8+ T cells have the best evidence linking them to MS pathology. Most CD20 expressing T cells are CD8+.

    ReplyDelete
    Replies
    1. yes I know about CD8 and CD20, I had done a diagram to show this point. I am not sure why it wasnt posted.

      However, dimethyl fumarate/Tecfidera apparently depletes CD8 T cells well...so why isnt it more active drug if CD8s are the main target?

      Delete
    2. I think the main reason anti-CD20 therapies work is because they deplete B cells. I also think an extra benefit is depletion of CD8+ T cells. My guess is that while anti-CD19 works well, it doesn't work as well as anti-CD20.

      Delete
  2. From the Atara Bio example and the antiretrovirals one -which, apart from AZT do not work against EBV- we maybe need to see again the theory of T cell exhaustion.
    Yes, B cells can go wild but you have zoomed too close and miss the bigger picture.

    ReplyDelete
  3. You have zoomed too close and miss the bigger picture...

    Please enlighten me what I am missing.

    Atara Bio is using CD8 T cells against EBV. THe problem they are not using autologous cells,. They may be MHC matched otherwise they will not work, but there is mismatch meeting that thhey may work but could recognise the new host as an invader and cause graft verses host issues,

    ReplyDelete
    Replies
    1. Hypothesis: Multiple sclerosis is caused by three-hits, strictly in order, in genetically susceptible persons

      1) a clinic-epidemiological model of multiple sclerosis as a rare late complication of two sequential infections (with the temporal sequence of infections being important); 2) a proposal that the first event is helminthic infection with Enterobius Vermicularis, and the second is Epstein Barr Virus infection; and 3) a proposal for a testable biological mechanism, involving T-Cell exhaustion for Epstein-Barr Virus protein LMP2A.

      https://www.ncbi.nlm.nih.gov/pubmed/30015080?dopt=Abstract

      Delete
    2. MD your main argument is that DMF depletes CD8 Tcells well and that does not change the course of MS.
      It could be that DMF starvs out the weakest part, one that was already out of function (considering the mechanism of action of DMF). The effects of depletion are not apparent because they would be the same as a not proper function...autoimmunity.
      Atara Bio and HAART do exactly what is needed. Reconstitute the action of CD8 T cells.

      Delete
    3. "but could recognise the new host as an invader and cause graft verses host issues'

      No chance of this..(knock on wood)FDA and EMA breakthrough approved..and the "Factory" already built.

      http://investors.atarabio.com/news-releases/news-release-details/atara-biotherapeutics-opens-state-art-operations-and


      "Factory

      Delete
    4. To add to my arguments above, maybe this is why intermittent fasting works in MS, because it helps with a partial reconstitution of Tcell function (considering what int. fasting does).

      Moreover, there are studies that report that patients with Lupus do not get easily infected by HIV, and HAART makes Lupus worse. (I can add the studies if you want to). However, it seems to help with MS. Could it be that Lupus and MS are an overdrive/underdrive of CD8 T cells (knowing that CD8 T cells are playing a major role in HIV)?

      MD I would really appreciate your thoughts.

      Delete

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