Monday, 6 February 2017

Is MS a T cell-Mediated disease

We made a suggestion that the B memory cell was important in MS. 

http://multiple-sclerosis-research.blogspot.com/2017/02/ms-is-b-cell-disease-and-memory-b-cells.html

CLICK TO READ

However, the reviewer was spitting blood that we did not mention T cells enough times and thought that the review was a bit biased.


Sure it has biased...as it is any opinion piece. If we did not take a stance, it could become a love-in and we would say everything is because of T cells.....no-one would bat an eyelid and we would keep on developing T cell treatments that have been pretty poor at controlling MS, but very good at treating EAE.

There were more than enough references compared to the 75 limit and to give a T cell-centric opinion on all treatments to appease someone, who frankly was never going to listen, or change or question their own pre-conceptions.


Sure all MS drugs affect T cells in some way, but we need to be abit more specific than that,  as we know that the level of CD4 and CD8 depletion does not associate with relapses.  

However, we believe that the disease causing cells must be antigen activated (i.e. in the primed CD45RO positive) T cell pool. 

See last weeks post as this is the basis for this post.
http://multiple-sclerosis-research.blogspot.com/2017/02/rebound-after-natalizumab-show-memory.html

However to make the referee happier we should have gone through the treatments one by one, to do the same type of search that we did to look for memory B cell activity, as we were asked to do by a blogger.

T cells likewise have T cell memory cells.

Therefore, we took the view that the T cells harboring the pathogenic cells would be in the CD4 or CD8 population that express CD45RO (a memory marker) and do not express CD45RA (antigen-inexpertienced cell marker) or CD62L (an adhesion molecule involved in getting cells into the lymph nodes) but express high levels of CD44 (to get the T cells into tissues including the brain. 

If you accept this, some won't so please read this recent post, then the important pathogenic cells will reside within the effector memory T cell population and not the naive or central memory T cell populations (CCR7+)

We then went through the current MS drugs and see how blood levels correlate with the idea that MS is associated with effector memory T cell levles.  We searched on the "name of the drug" and "CD45RO/memory T cell" just like we had searched on "CD27/memory B cell".


The search revealed a positive correlation of B memory cell function with all MS drugs and was this was most clear in the highly active DMT.

Sure these drugs can affect T cells, but what about effects on the memory cells.

If we take the same argument for T memory cells, what do we get?

_____________________________________________  
                  CD4 memory T    CD19, CD27 memory B
_____________________________________________

Alemtuzumab     NO                   YES
Anti CD20          NO                   YES
Natalizumab       NO                   YES
Mitoxantrone      NO                   YES
Daclizumab   MARGINAL NO  YES Marginal
DMF                  YES                   YES 
Beta Interferon YES/NO             YES
Copaxone           NO                    YES  
_____________________________________________
                                                                                                        Noooooooooooooooooooooooooo...it can't be says MrT.


Want to look at the data yourself, here you go!


ALEMTUZUMAB-NO
Expect decrease in memory T cells if important. Whilst naive T cells get it,
 (effector) memory cells (bottom left graph) increase! At least CD4 memory cells do. Don't they?!....Oops



Jones JL, Thompson SA, Loh P, Davies JL, Tuohy OC, Curry AJ, Azzopardi L, Hill-Cawthorne G, Fahey MT, Compston A, Coles AJ. Human autoimmunity after lymphocyte depletion is caused by homeostatic T-cell proliferation. Proc Natl Acad Sci U S A. 2013 Dec 10;110(50):20200-5.


One of many, many references. Where is the contradiction?

CD20-specific antibodies-NO
Expect decrease in memory T cells if important.

There are a few T cells that get depleted, but the T cell population doesn't go down enough to suggest there was any effect of the memory T cell subset. So no direct effect on T cells can be linked to T cell number...Next 

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; 193:580-6.

CD49d-Natalizumab-NO
Expect increase of in memory T cells as trapped in blood if important.
No effect. Next!





Planas R, Jelčić I, Schippling S, Martin R, Sospedra M. Natalizumab treatment perturbs memory- and marginal zone-like B-cell homing in secondary lymphoid organs in multiple sclerosis. Eur J Immunol. 2012; 42:790-8.

Mitoxantrone-NO
Expect decrease in memory T cells if important. If fact most T cells are not affected. Its not bad at killing B cells though. Next.

Pelfrey CM, Cotleur AC, Zamor N, Lee JC, Fox RJ.Immunological studies of mitoxantrone in primary progressive MS. J Neuroimmunol. 2006 ;175(1-2):192-9.


Cladribine-NOT COMPELLING 


Fingolimod-NO Expect decrease in memory T cells if important
As we would expect the cells expressing CCR7 are trapped in the lymph glands and the effector memory population increases. S
o the T cell idea is not very compelling when looking in the bloods of people treated with the highly active drugs. 



Song ZY, Yamasaki R, Kawano Y, Sato S, Masaki K, Yoshimura S, Matsuse D, Murai H, Matsushita T, Kira J. Peripheral blood T cell dynamics predict relapse in multiple sclerosis patients on fingolimod. PLoS One. 2015;10(4):e0124923.

Claes N, Dhaeze T, Fraussen J, Broux B, Van Wijmeersch B, Stinissen P, Hupperts R, Hellings N, Somers V.Compositional changes of B and T cell subtypes during fingolimod treatment in multiple sclerosis patients: a 12-month follow-up study.PLoS One. 2014 Oct 31;9(10):e111115 .

What if we look at the moderately effective DMT.

Dimethyl Fumarate-YES-Hurray!!!! Expect decrease in memory T cells if important. Yeah memory CD4 and CD8  T cells go down


Gross CC, Schulte-Mecklenbeck A, Klinsing S, Posevitz-Fejfár A, Wiendl H, Klotz L. Dimethyl fumarate treatment alters circulating T helper cell subsets in multiple sclerosis.Neurol Neuroimmunol Neuroinflamm. 2015;3(1):e183

Daclizumab-MARGINAL
Expect decrease in memory T cells if important. Looks like not much and mainly in the no camp. 
Lanio N, Sarmiento E, Gallego A, Navarro J, Palomo J, Fernandez-Yañez J, Ruiz M, Fernandez-Cruz E, Carbone J. Kinetics of functionally distinct T-lymphocyte subsets in heart transplant recipients after induction therapy with anti-CD25 monoclonal antibodies. Transpl Immunol. 2013;28(4):176-82.

This is not MS, The data is probably tucked away in ECTRIMS poster, never to see the light of day, I only served abstracts and may have missed it

Beta Interferon-YES
Expect decrease in memory T cells if important. Refreshing to know that beta interferon supports the view


Zafranskaya M, Oschmann P, Engel R, Weishaupt A, van Noort JM, Jomaa H, Eberl M. Interferon-beta therapy reduces CD4+ and CD8+ T-cell reactivity in multiple sclerosis. Immunology. 2007; 121:29-39.

Hang-on or does it : NO
Avolio C, Ruggieri M, Cafforio P, Giuliani F, Silvestris F, Dammacco F, Livrea P, Trojano M. LFA-1 expression on CD4(+)CD45RO(+) peripheral blood T-lymphocytes in RR MS: effects induced by rIFNbeta-1a. J Neurol Sci. 2001;186(1-2):65-73


Copaxone-NO
Expect decrease in memory T cells if important
Lastly the drug that has had every mechanism under the sun:-), but maybe not this one as....Yikes it does nothing or makes the number of memory T cells go up.
Carrieri PB, Carbone F, Perna F, Bruzzese D, La Rocca C, Galgani M, Montella S, Petracca M, Florio C, Maniscalco GT, Spitaleri DL, Iuliano G, Tedeschi G, Della Corte M, Bonavita S, Matarese G. Longitudinal assessment of immuno-metabolic parameters in multiple sclerosis patients during treatment with glatiramer acetate .Metabolism. 2015;64:1112-21

Atacicept (makes MS worse)-YES SORT OF
Expect Increase in memory T cells if important

What does it do in EAE?-Not quite sure but data suggests it makes it better, so not in MS

Zhou X, Xia Z, Lan Q, et al. BAFF promotes Th17 cells and aggravates experimental autoimmune encephalomyelitis. PLoS One. 2011;6:e23629

The hypothesis was that BAFF makes autoimmunity worse and makes a Th1 response. A transgenic mouse making BAFF made more Th17 and EAE was a little worse, where as BAFF knockout mice made fewer Th17 and was a little better and got EAE despite having no B cells. So problem when you do experiment, before you know the result, you don't always get what happens in MS.

Next follow-up and TACI-Ig (atacicept) causes a decrease in Th1 and Th17, so wrong way to explain MS result using a Th1/Th17 idea but low and behold there was an increase in memory T cells.

So if I presented this to the referee as the other half of the story would they buy it? 

Would they block the B cells stuff to Ensure the T cell stuff is never read? 

Would it have been worth the extra few references?

What references do we need to add contradict this view? 

Would someone publish this?  

Would the referee accept that their bubble bursts?

More on this tomorrow.

10 comments:

  1. I've been with you on the memory B cells (child's been on Rituxan 3.5 years with spectacular turnaround), but appreciate all the time and effort put into this.
    Perhaps it will do some good, at least for patients and students. I suspect some researchers are firmly wedded to their "truths", and will ignore.

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  2. Any reason Dimethyl Fumarate isnt in the table even though its listed later as a yes?

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  3. This B-cell theory is very compelling MD in RRMS/inflammation. Thanks for your passionate & hard work in presenting and congratulations on your publication.

    The problem that I see is that none of the above drugs effectively stop the progression of MS whatsoever. What is the use of comparing any of these drugs if they do not effectively halt the progression of the disease? Obviously, the B-cell theory is important in relapses/inflammation, but it appears but something else is causing progression of the disease (A1 astrocytes, hot microglia or neuronal cellular dysfunction) to which B-cells (or T-cells) seemingly play a much smaller role.

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    Replies
    1. Maybe... maybe not, if I say that B cells enter CNS and form the B cell follicles and plasma cells and they secrete antibody and make cytokines and these antibodies attack the nerves or they activate the microglial that then make the A1 astrocytes that damage the demyelinated nerves, but they are not blocked because none of the current licenced DMT get into the CNS to target the B cells...can you argue against this?

      We have repeated said that we need to target multple componenets to target damaging elements of MS.

      What happens when we use the big gun agents early in MS.

      Likewise how do we target cells in the CNS, the approach of using antibodies is not the way to go they just dont get in..

      Delete
    2. "The problem that I see is that none of the above drugs effectively stop the progression of MS whatsoever."

      Which will depend on how early you treat. The pwMS treated very early in their disease with alemtuzumab may reveal how effective very early DMT can be in stopping/slowing progression.

      Delete
    3. So MDs for those of us who have missed the boat, our best chance at present is cladribine?

      Delete
    4. A combination is likely to be the best option but pharma dont like combinations but look at HIV for example, it use to be a death sentance but with a poly pill the virus can be held at bay for many people.

      To answer your question, there may be some advantage because unlike and drug it can get into the CNS, about a quarter of the blood levels, it does not need cell division to act unlike cyctostatic drugs, and it has the potential to kill plasma cells and it may reduce OCB in some people. This needs further study.

      Delete
  4. Any thoughts if this article could show a possible way T cells still could be the cause: MNT : T cell type that promotes damaging immune response discovered
    http://www.medicalnewstoday.com/articles/315627.php

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    Replies
    1. https://www.ncbi.nlm.nih.gov/pubmed/28150777

      Thanks very interesting.


      For T cells there is a subpopulation of cell labeled Follicular B helper T cells https://en.wikipedia.org/wiki/Follicular_B_helper_T_cells

      These help B cells produce antibody..what this study is saying is that there is a subset of T cells they call peripheral peripheral helper' found in the joint that help B cells to produce antibody. However central problem is the B cells and the T cell facilitates. Immunology works in tandem so it it is not going to be one or the other but both.

      Delete

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