Professor & patients' paper on the solvable biological challenge of ME/CFS: reader-friendly version
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Making Sense of Mark Davis' findings

Discussion in 'Latest ME/CFS Research' started by Cam Newton, Aug 15, 2017.

  1. Cam Newton

    Cam Newton

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    I'm not sure how much in detail this has been discussed but I'd like to have a discussion about Mark Davis' findings that he revealed at the Stanford ME/CFS symposium, on Saturday.

    Here is the direct link:

    upload_2017-8-15_15-31-18.png

    As an initial disclaimer, I am the furthest thing from an expert in immunology. I've been trying to learn about it over the past few days in order to make sense of Mark's findings.

    Essentially, he found clonal expansion of CD8+ (cytotoxic) T-cells in ME/CFS patients. If I understand it correctly, the body will clone these cytotoxic T-cells when it needs to build an army to fight an antigen. This also happens to patients that have other diseases like cancer, MS, lyme disease, and probably many more. Mark Davis did say that it is possible these cytotoxic T-cells are evidence that ME/CFS is an autoimmune disease and that these cytotoxic T-cells may be targeting the self; hence autoimmunity. He mentioned the microglia as a possible errand target for the cytotoxic T-cells.

    Here are some thoughts. Whatever is happening with these T-cells must make sense within the context of how some patients respond and recover from ME/CFS when given Rituximab and/or cyclophosphamide (the CycloME study hasn't been released but according to the researchers there are many responders, and cyclo is "at least" as promising as Rituximab). Could the large number of cytotoxic T-cells be evidence of an ongoing viral infection? I doubt it, since if it were an ongoing viral infection the Rituximab would wipe it out very quickly, instead of a long lag-time (according to Fluge and Mella). It seems like the clonal expansion of cytotoxic T-cells could have been initially caused by infections; since ME/CFS is often caused by an initial infection. Then the cells either hang around because they got confused and found a new self target by mistake, or the cytotoxic T-cells didn't decline back to healthy levels (around 10% of total T-cells according to Dr. Davis, if I am understanding that correctly) for some unknown reason. Could the success of cyclo be in that it reduces the number of T-cells, thus killing cytotoxic cells and re-starting the T-cell population? I believe cylco has an immunostimulatory effect in low dosages and an immunosuppresive effect in higher dosages. Below is a paper showing that 100mg of cyclo per day can significantly decrease T and B cell counts.
    http://onlinelibrary.wiley.com/doi/10.1002/art.1780180113/pdf

    Is the 1 to 1.5g of cyclo given every 4 weeks (in the CycloME trial) enough to also significantly decrease T and B cell counts? It seems like it, otherwise, there wouldn't be massive risks of infections caused by the therapy. Could the response, by some patients, be due to this reset of T and B cell populations? Rituximab only effects B-cells but B-cells and T-cells do work together so Rituximab would still impact the function of T-cells, I think?

    Does anyone else have any thoughts? Am I completely misunderstanding this stuff?

    Cheers,
    Cam
     

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  2. lansbergen

    lansbergen Senior Member

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    First question. Are they toxic enough.
     
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  3. dannybex

    dannybex Senior Member

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  4. Murph

    Murph :)

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    I am probably even further from an immunology expert than you, but this research makes me excited about cyclo. Cyclo hits T cells and B cells. Rituximab just hits B cells.

    Fluge and Mella have dropped a few hints that Cyclo may be even more effective than Rituximab. The fact T cells are implicated lends credence to those hints.

    Also, if you take out T cells, will the disease come back like it (often) does after Rituximab? The fact they extended their Phase II trial by 6 months could be a clue that effects were more long-lasting than they expected. Best case scenario is that killing the T cells resets the illness altogether! (worst case scenario is the time extension was necessary to keep track of nasty side effects.)

    Getting back upstream in the chain of causation is still a mystery though. Why are the t cells being cloned? My laypersons understanding is that T cells clone themselves if they are the kind of t cells that can attack an antigen that is present. It certainly leaves open the possibility of an antigen being present. Or some sort of signal that an antigen would produce to initiate cloning is present, or the t cells have misidentifed self as an antigen. I can't choose between these three options, and they have different implications for whether killing T cells will be anythign like a permanent fix.
     
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  5. ljimbo423

    ljimbo423 Senior Member

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    Mark Davis said there almost certainly is an antigen present, then said, there maybe multiple antigens present but there certainly are some.

    That is the reason for the t cell expansion/cloning. He also said they are looking into the "specificity" of those t cells, that may reveal both a specific pathogen and tissue target. That sounds like exciting research!!:)

    Jim
     
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  6. kelly8

    kelly8

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    I'm interested in the "hit" he mentioned for the antigen. When do we get to find out what that is?
     
  7. M Paine

    M Paine Senior Member

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  8. Vicki Cole

    Vicki Cole

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    Can anyone tell me how Naviaux's cdr fits in with Davis' ideas? I'm trying so hard to get my head around all of this ()! Thanks.
     
  9. Bander

    Bander

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    Let me attempt a gross oversimplification based on my limited understanding of all of this. Davis' work points towards a specific pathogen that has triggered a distinctive immune response in cfs patients. That doesn't mean the pathogen is still around. But "something is stirring up" the immune system in a specific way and it is correlated with disease severity.

    You could imagine three scenarios:
    1. The body is battling a pathogen that is still in the system and the work it is doing is important to keep the disease at bay.
    2. There is a pathogen that the body is battling, but the immune response has triggered an attack on some "self peptide" that is causing extra problems (i.e., the immune system is also attacking some tissue in the body--hence, autoimmunity).
    3. There was a pathogen that triggered an immune response in the past and it has mostly disappeared, but for some reason the body is stuck in battle mode and is continuing to pump out chemicals that are making the patient ill.
    Very few people seem to believe #1. When Naviaux was asked about it (whether it could be dangerous to stop this immune response), he didn't seem to think that was a great concern. So most people are in the #2 or #3 camp. The first step of Naviaux's program is to "remove the CDR trigger if it is still present." So if it's scenario #2, then perhaps we have to clear the pathogen before moving forward. I find #3 the most interesting possibility. Perhaps the antigen is gone or greatly reduced, but somehow the immune system never recognized this. That's a lot of what Naviaux's theory is about. The autoimmune response can itself be causing the metabolic problems that we see because the healing process did not complete it's normal cycle. So Naviaux's second step would be to counter the metabolic issues ("refill the metabolic tank") and then use some other drug to try to complete the healing cycle in step 3 (complete the healing process and return to normal).

    I don't understand the Rituximab theory very well, but I get the sense that it is related to possibility #3 with the idea that perhaps killing off a generation of immature B-cells can interrupt the broken immune response, although it takes many months to work through that process (a little bit like powering down your computer and turning it back on and hoping it boots back up in a better state).

    I welcome corrections/clarifications from others who understand this better than I do.
     
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  10. Simon

    Simon

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    Nice line.
    I've now blogged about this work here, PR thread on it here. Hope you don't mind, I borrowed your army line :)
     
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  11. Vicki Cole

    Vicki Cole

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    Thank you so much. My mind is frazzled and this has helped a lot!
     
  12. M Paine

    M Paine Senior Member

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    I would like to know what method they have used to isolate t cells that has undergone mass cloning, and how they have isolated a common tcr across patients. If it turns out to be a valid finding, that's a massive achievement.

    *Edit, just read Simons blog post. Answered most my questions. Nice work.
     
    Last edited: Aug 18, 2017
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  13. Cam Newton

    Cam Newton

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    Thanks for the post. Obviously, I am seeing things through rose-colored glasses but I also get the feeling that cyclo has been more successful than Rituximab.

    For option #2, it is my understanding that there doesn't have to be an actual pathogen still in the body for the body to target itself. Say an initial infection triggers massive clonal expansion of CB8+ cells, these cells kill off the infection (in my case it was mono) but the cells start to target the self erroneously. And since all these CD8+ cells are "attacking" the self, they are not dying off like what normally happens after an infection.

    Regardless, I think, over next year we could make massive steps forward in understanding. The CycloME trial plus Mark Davis' continued work could be gigantic. Mark seemed quite confident he could continue down this rabbit hole that he discovered.

    Fingers crossed.
     
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