Friday, 14 September 2018

Wakey-wakey people. Read this and it all becomes clear. MS gets simpler

If you are a regular reader of the blog, you may think this work is old hat. This is because you have been watching these ideas evolve over the past year.

Hopefully for others who have not been following us, this could be a day of revelation and the Penny may finally Drop (The penny dropped is a casual idiom outside the United States used to mean a person has belatedly put two and two together or understood something).

If you are a nurse or a neurologist or Junior Doctor, and only read one paper (Click on link below for full paper) a year give this one a read. It may help you conceptualise MS and its treatment better as "MS therapy just got easier".  

Send this post to your friends. Ask them for holes in the arguments.

If you are a person with MS, give it a read and ask questions if you don't understand. It may make your descisions of treatment easier.

However, for all you young-researchers (meaning mentally young even if old in body) out there...the old-ones are probably a lost cause as they are unlikely to want change their ways and will simply ignore this:-(.....Give this a read, spot the holes and the inconsistencies, but maybe look at your research in a different way. Try and disprove the ideas. 
For all of my adult working life...T cells have been considered to be the driver of autoimmunity. It has been forgotten that they were once called "helper" cells, because they help other cells to do things.

The Status Quo however, has been shattered by the development and efficacy of CD20 B cell depleting antibodies in MS. 

People have had to build the B lymphocyte into their world MS view. 

For many this has been done relecutantly and their MS World view has not really changed, as they consider that the antibody targets the few T cells that expess CD20. Alternatively they claim that B cells are simply acting as antigen presenting cells to activate T cells to be top dog

Although CD20 is expressed on a few T cells, they do not really express CD19, which is another B cell marker. However, CD19-depleting antibodies also work in MS, so they are probably not working directly via T cells. This needs to be brought into the MS World view. 

Maybe T cells are there to help B and other cells such as macrophages to be the Top Dogs in MS.

However, the success of ocrelizumab in MS, has meant that the companies want to create product awareness. As such I believe that they have sponsored numerous B cell reviews, such that leading clinical neuros have written them or perhaps put their name to reviews written for them:-(. 

In addition to be topical, researchers have produced loads and loads of B cell reviews also. 

However, they have one thing in common. This is besides often giving the trial results of the ocrelizumab phase III trials that is surely part of the marketing in the review.  

The thing they have in common is that they list a set of unrelated potential facts that provide essentially zero interpretation or insight:-(. 

Although, I do not wish to appear arrogant, companies perhaps can be excused for creating a boring read as they need to do bland, so they don't get accused of providing opinion, but the researchers/opinion leaders can surely do better. 

If you like your reads..bland then go no further, there is plenty of "bland" out there. 

However, we have given opinion and have fought with the reviewers to do so. Hopefully it will make you think and maybe it will explain some things. 

This is a review that some will like, it was one of MD2s favourite ones, but others, perhaps many others, will disagree as it may challenge their MS-World. Hopefully it will spur people to disprove the concepts and if they can, we can modify our views and move forward but it they can't then great too. 

(Read me)



ABSTRACT Although many suspected autoimmune diseases are thought to be T cell-mediated, the response to therapy indicates that depletion of B cells consistently inhibits disease activity. In multiple sclerosis, it appears that disease suppression is associated with the long-term reduction of memory B cells, which serves as a biomarker for disease activity in many other CD20+ B cell depletion-sensitive, autoimmune diseases. Following B cell-depletion, the rapid repopulation by transitional (immature) and naive (mature) B cells from the bone marrow masks the marked depletion and slow repopulation of lymphoid tissue-derived, memory B cells. This can provide long-term protection from a short treatment cycle. It seems that memory B cells, possibly via T cell stimulation, drive relapsing disease. However, their sequestration in ectopic follicles and the chronic activity of B cells and plasma cells in the central nervous system may drive progressive neurodegeneration directly via antigen-specific mechanisms or indirectly via glial–dependent mechanisms. Whilst unproven, Epstein-Barr virus may be an aetiological trigger of multiple sclerosis. This infects mature B cells, drives the production of memory B cells and possibly provides co-stimulatory signals promoting T cell-independent activation that breaks immune tolerance to generate autoreactivity. Thus, a memory B cell centric mechanism can integrate: potential aetiology, genetics, pathology and response to therapy in multiple sclerosis and other autoimmune conditions with ectopic B cell activation that are responsive to memory B cell depleting strategies.


If MS agents act in a similar fashion then treating MS just got easier. You only need to concern yourself about convenience, degree of efficacy and side-effect

Now read why animals may not be the answer

30 comments:

  1. Thanks for keeping your papers open-access. So, how come, at a journal with a reputation like Cell, they don't get good reviewers? As this clip on youtube says: The Essence Of Science In 60 Seconds (Richard Feynman)

    ReplyDelete
    Replies
    1. Good Reviewers

      (a) Some people are too lazy/busy to do things properly.
      If you dont know enough you need to do abit of reading so people don't

      (b) Some people are lemmings and so if you say the right thing they buy-it
      If you say something that goes against the grain they have problems

      (c) Some people are mates of the authors and even though it is supposed to be anonymous, they still belly up and don't review properly

      (d) Some people are frightened of giving a bad review to a big hitter

      (e) Some people are so star struck they give the big hitter a good review.

      I have seen examples of the above especially as you get to see the other reviewers comments.

      I can remember a paper of a "big swinger" opinion leader, where one referee said wonderful paper...brown nose, brown nose. The paper was a pile of tosh with loads of things that didnt make sense and loads of mistakes

      I have heard where some reviewers contact people and tell them they are reviewing the paper.

      Although you are suppose to declare conflicts there is no doubt that some people get their mates to review stuff. e.g. in the paper below the handling editor works with the author. How can there be no conflict even if the editor thinks that they can be impartial.

      I spend my life battling with the (b) type. In this review the referees didn't like the mentioning of the EBV as they thought it was too speculative. But at least they didn't try to get us to remove this.
      The referee of the original memory B cell paper wanted us to remove mention of memory B cells. (I worked out who they were and knew that they were doing the same work, so they were trying to stop publication :-()

      Delete
    2. "Good Reviewers"

      Hmmm..wondering what thoughts/feedback Pender had of this paper.

      Delete
  2. Thanks for the link to the paper. As you state, targeting B-cells inside the CNS and lymphoid follicles in the meninges may be a treatment of progressive disease. The intrathecal rituximab trial at the NIH for secondary progressive MS failed due to presumably poor penetration of the mab into secondary lymphoid follicles how might we get better B-cell depletion inside the CNS?

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    1. Maybe but I think there are more reasons and I am not convinced the antibody cells are resident within the follicles. In the lymphoid tissue to my surprise plasma cells and memory cells leave once formed and reside elsewhere.

      However first thing is if the target is plasma cells then rituximab or other CD20 antibodies are no good because plasma cells and plasma blasts are CD20 negative. You need to target something like CD138. I can't believe trials went ahead with the view of killing plasma cells. Thanks not understanding Immunology 101. If you get rid of memory cells do you get rid of cells producing growth factors required for plasma cell survival. Maybe something in this but not definative.

      Next the intrathecal route. The flow is down and out. If the pathologists are correct which I doubt and that the B cells are hiding in the sulci of the brain, then the intrathecal route is not the best as stuff doesnt get to the brain. This is the logic of intrathecal baclofen pumps. Get drug into spinal cord for effect and avoid activity in the brain to limit side-effect. I have heard someone suggesting to an intraventricular delivery..equally bonkers and who wants holes drilled through their skulls.

      Next effector function. Antibodies may not kill directly and either need free complement to fix complement and kill cells or for some they need cells such as natural killer cells and neutrophils to kill. These may be lacking. Therefore antibodies may not be good targetting method.

      How to get B cell targeting.

      Best to use a small molecule killer. One approach may be CNS penetrant bruton tyrosine kinase inhibitor and the other approach would be a proteosome inhibitor.

      My money will be on these agents. The reason is that they are used to kill B cell CNS lymphomas. So a pulsed therapy mat do the trick.

      We (ProfG & NDG) aim to do a small trial with a one of these,

      Funding is in place and the protocol is more or less finalised so we should be good to go soon.

      Fingers crossed

      An approach would be allogeneic haematopoetic stem cells. They get in brain and cause graft verses host disease and kill the immune cells in the brain. At a recent meeting and heard of a person who had 2 autologous (own cells) HSCT that did not work and then and allogeneic (cells from someone else) and MS stopped.

      The sexy science approach would be through the use of killable (so you can get rid of them) plasma cell specific CAR T therapy

      Delete
    2. MD: Plasma cells can reside for years in the intestinal wall, why do you think it isn't so within the brain?

      http://jem.rupress.org/content/early/2017/01/17/jem.20161590

      Delete
    3. Plasma cells do hang around for a long time hence stable OCB. They presumably get growth factor stimulation (folliclular helper cells?), because put a Plasma cell in culture without growth factors and they are dead as a dodo in days

      Delete
  3. I did a course of intrathecal and intravenous Rituxan 5 years ago for RRMS. I’ve had no other MS therapies. Recent MRI shows “very mild progression over interval”...just two small new lesions. My MRI-documented progression between 2012 & 2013 was significantly worse. I think i.t. Rituxan works for RRMS (and CNS cancers). I’m in the middle of another course right now.

    ReplyDelete
  4. "Expression Pattern of Myelin-Related Apolipoprotein D in Human Multiple Sclerosis Lesions"

    Mixed results

    The present study is, to our knowledge, the first to examine
    CNS histopathological findings in MS patients after
    allo-HSCT. Despite the procedure, active demyelination
    and inflammation persisted, indicating the failure
    of allo-HSCT to halt the MS disease activity, at least during
    the follow-up period in these patients. This failure
    may be attributed to several possibilities.
    First, the persistence of recipient immune cells in the
    brain may fuel the MS activities. This possibility is supported
    by our previous finding in which fluorescent in situ
    hybridization analysis of sex chromosomes of cells in a female
    MS patient who received allo-HSCT from amale donor
    (case 1 in Table 1) revealed that, although only donor
    blood cells were present in the peripheral circulation
    most CD45 and CD68 cells within the brain were still
    of the female recipient’s origin.15 Although complete chimerism
    of circulating leukocytes can be optimally achieved
    by allo-HSCT, the conditioning immunosuppressive treatment
    may have much less effect on the cells trapped or
    resident within the CNS.22-24 In support, Mondria et al25
    examined 2 markers indicative of lymphocyte activation
    in the cerebrospinal fluid, sCD27, and oligoclonal IgG
    bands, and found that these were still evident 6 to 9 months
    after whole-body immune ablation inMSsubjects. The authors
    concluded that complete eradication of activated lymphocytes
    from the CNS had not been achieved despite intense
    immunoablation.
    Second, GVH reaction could theoretically induce alloimmune
    damage to the brain9,10,25 and may complicate the
    pathologic processes ofMSafter allo-HSCT.26,27 In the present
    study, all the patients (including the MS patients and
    non-MS patients with normal-appearing brains) developed
    histopathologically confirmedGVHdisease after allo-
    HSCT, involving the skin, gut, or liver. Graft-vs-host disease
    is associated with a cytokine storm and T-cell activation,
    which induces the complex immune reactions that interact
    with the pathological processes of MS.27,28 The present
    study demonstrated increased diffuse infiltration of T cells
    and macrophages/microglia within the normal-appearing
    brains of non-MS patients after allo-HSCT, which would
    be consistent with theGVHreaction after allo-HSCT. Nevertheless,
    the contribution of GVH disease to the demyelinating
    activity of MS may be minor in the present study
    because (1) at least 1 patient (case 1 in Table 1) showed
    clinical evidence of MS progression before the development
    of GVH disease15; (2) there was no obvious demyelination
    in the non-MS allo-HSCT recipients, although their
    brains showed mild and diffuse inflammation; and (3) demyelination
    and neurodegeneration were active even with
    marked suppression of the inflammatory activity inMSpatients
    who received autologous HSCT.7
    Third, the failure to arrest MS progression has been
    often attributed to studying patients in whomMS has progressed
    into advanced stages.7,29,30 This possibility is unlikely
    in the present study because one of our patients
    (case 1 in Table 1) had a pretransplantation Expanded
    Disability Status Scale score of 2.0 and another patient
    (case 4 in Table 1) was asymptomatic before allo-HSCT.
    Therefore, the failure of allo-HSCT may occur even in
    less advanced MS

    https://www.ncbi.nlm.nih.gov/pubmed/20558390

    ReplyDelete
    Replies
    1. MS lesions once established with progressive MS will take their course

      Delete
    2. Thanks
      Copy paste the title wrong

      Obrigado

      Delete
  5. This patient did not experience worsening of her MS symptoms during either the acute phase of BMT or through 14

    months of follow-up. Furthermore, she has noted sympto-matic improvement and neurological examination is now normal
    other than the pale right optic nerve. Her MRI scanremains stable with no evidence of new lesions.

    https://www.ncbi.nlm.nih.gov/pubmed/9051253

    ReplyDelete
  6. Abstract We describe a 57-year-old man, affected by
    large granular lymphocyte (LGL) leukemia and concomitant
    primary progressive multiple sclerosis (MS), treated
    with allogeneic hematopoietic stem cell transplantation
    (HSCT) from an HLA-identical sibling. The patient was
    conditioned with fludarabine, busulphan, and cyclophosphamide.
    Graft-versus-host disease (GVHD) prophylaxis
    consisted of cyclosporine and short-term methotrexate. At
    3 years follow-up, the patient is in complete remission of
    LGL with a marked improvement in neurological conditions.
    This is the first case of allogeneic HSCT in a patient
    with LGL leukemia and concomitant primary progressive
    MS. Allogeneic HSCT, performed in our patient to cure
    the lymphoproliferative disorder, improved the clinical
    course of MS.

    https://www.ncbi.nlm.nih.gov/pubmed/14648027

    ReplyDelete
  7. Multiple sclerosis (MS) is thought to be an autoimmune disease in which activated T-cells initiate a
    macrophage mediated destruction of CNS myelin. Bone marrow transplantation (BMT) is currently
    being evaluated in the treatment of MS in patients with aggressive disease activity. Autologous BMT
    could potentially reset the immune response to myelin antigens leading to immune tolerance and
    decreased disease activity. Allogeneic transplantation could reconstitute the immune system potentially
    arresting the progression of autoimmune disease. The purpose of this paper is to report a patient with
    MS who underwent allogeneic BMT for chronic myelogenous leukemia (CML) and showed continued
    evidence of active demyelinating disease by clinical and radiologic criteria over a period of two years.
    While this is only a single case report with inherent limitations, it suggests that the immune mediated
    destruction of CNS myelin in MS may not be prevented or aborted by immune system reconstitution,
    and is consistent with the idea that immune mediated tissue destruction in MS could be targeted
    against an abnormal antigen.

    Multiple Sclerosis 2007; 13: 1071–1075. http://msj.sagepub.com

    ReplyDelete
    Replies
    1. Yep HSCT is is not the whole answer for progressive MS

      Delete
  8. Cart cell

    Give you 250 000 Ferritin

    (he said they have to redesigned the monitor instruments)

    Cytokine release syndrome

    Have talk to Stephan A. Grupp the first to test Cart cell in an 5 year

    old girl with ALL and he said the therapy is maninly for pediatric use

    Obrigado

    at this moment

    ReplyDelete
    Replies
    1. Depleting your B cell response for every in notagood idea especially in chiij

      Delete
    2. They use to give Rituximab after HSCT in Mexico..then
      they realized how much more can B cells be depleted..?
      And the answer was none..none more depleted..so they stopped
      the Rituximab.
      Like the Spinal Tap..none more black joke
      https://www.youtube.com/watch?v=mHy6_vQueLI

      Delete
  9. "that breaks immune tolerance to generate autoreactivity"

    Then why a relapse doesn't culminate in full CNS destruction?

    How are B cells sensitized to CNS stuff since BBB keep them out of limits?

    Why aren't B cells sensitized to Peripheral Nervous System where the barrier is weaker? Neurons, axons, Schwann cells are there to offer antigens too.

    ReplyDelete
    Replies
    1. B cell specificities are randomly created in the blood marrow. They do not need to be exposed to CNS in order to generate B cell receptors specific for it. Indeed, B cells with auto-reactive receptors are generated frequently. The majority is eliminated through various processes before the mature, but a significant amount of B cell released to the blood are still potentially autoreactive. The general idea is that T cell tolerance holds this back, so it doesn't develop into auto-immunity. If you however bypass the T cell inhibition, there might be trouble..

      Delete
    2. "The general idea is that T cell tolerance holds this back, so it doesn't develop into auto-immunity. If you however bypass the T cell inhibition, there might be trouble"

      I agree with you, but I am not sure MD and the team agrees too (bad for them IMO).
      Barts team tries too much to gain their space in the field that they just refuse to see a lot of good quality evidence about the mechanism of T cells. Its either only B cells or it isnt at all. They quote themselves a lot too!

      Delete
    3. What about the first question? How can autoreactivity be self limiting in remissions and then again active in relapses?

      Delete
    4. First question. Regulation.
      Your immune system fights infection and goes quiet, regulation and lack of target antigen. I guess..

      Delete
    5. BBB keeps stuff out of CNS, but there are drainage pathways taking stuff to lymphoid tissues. That is where immune responses are formed, tissues are not designed to start immune responses.

      Delete
    6. Peripheral nerves...Peripherally expressed antigens are more likely to trigger depletion of autoreactivity than antigen that are sequenstered away from the immune system (simple immune theory)

      Delete
    7. "They refuse to see a lot of good quality evidence about the mechanism of T cells"

      What papers do you want me to talk about? (EAE is T cell mediated)

      Regulating T cells stopping autoimmunity from devloping..absolutely no problem with that.

      In my Opinion (MO?) "They quote themselves a lot too!". Yep part of the function of the blog is is to document the stuff we do. Quote us...yep sadly some people dont quote us when they should...that's science. DrLove thinks failure to accurately cite others work (to make your work seem novel) is a form of science fraud, aimed at misleading the readers.

      "It's either only B cells or it isnt at all". Sometimes I take the more extreme position to push people to think about their happy little dogma world. B cells are unlikely to exist in a void. However I ask again, what do you consider "good quality evidence" about the mechanism of T cells? (in humans). Please list. The latest paper by Roland Martin had T cels at the core? But go on give me something to get my teeth into. Maybe we could get VV to critique too. Will we agree.

      Delete
  10. "Why aren't B cells sensitized to Peripheral Nervous System where the barrier is weaker?"

    In MS the B cells produce antibody for the brain so that's where they go.
    In RA they go to synovial joints..in Lupus the kidneys.

    ReplyDelete
    Replies
    1. May i remind you that none of the diseases you mention has been proved autoimmune or B cell driven. Despite known comorbidity, these diseases hold discrete territories for a life time, something hard to believe for B cell specificities that are randomly created in the blood marrow as Rune Alexander pointed above.

      Delete
    2. But random generated they are...the immune sytsem is an amazing thing that it essentailly can make a response to anything, that you havent encountered. This makes the human population resilient

      Delete

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