Monday, 28 March 2016

ResearchSpeak & GrandChallenges (7): how do anti-B cell therapies work?

Why are plasma cells potentially so important in MS? #ResearchSpeak #GrandChallenges #MSBlog #MSResearch

It is clear that B cells play a central role in pathogenesis of MS, could the role for plasma cells be even bigger?

1. MS has not be seen in people who don't make immunoglobulins due to rare genetic disorders (agammaglobulinaemia).

2. Oligoclonal IgG bands are invariably found in the cerebrospinal fluid (CSF) and brain/spinal tissues of MSers. These immunoglobulin bands have been highly selected; in other words whatever is driving their production is getting help from other cells (antigen presenting cells and T cells). This selection process is typically seen with infections or foreign antigens (proteins).

"If we can uncover what these OCBS are reacting with we will uncover the cause of MS."

MSers who don't have these oligoclonal bands have a more benign course; this applies to MSers with relapse-onset MS and PPMS.

"OCB-negative MSers don't have 'classic MS' and if I had my way they would be given a separate diagnosis or at a minimum a definitive MS should be delayed; this is particularly important when diagnosing PPMS! This is another reason why lumbar punctures and spinal fluid analysis should be done in all MSers. You only get one chance not to make the diagnosis of MS and that is in the beginning, or the diagnostic phase, of the disease. Spinal fluid analysis helps you exclude other conditions and tells you if you have OCBs or not."

3. B-cell follicles, were the B-cells mature and become antibody factories or plasma cells, are found in CNS of MSers. These are ectopic follicles as they are normally found in lymph nodes and the spleen. These follicles appear to be more common in progressive MSers and appear to be driving the cortical, or gray matter, pathology. The current thinking is the gray matter pathology is what drives the clinically-apparent progressive phase of the disease.

4. Pathological studies show immunoglobulin deposits in the brains of MSers and associated complement activation. Complement is one of the molecules that certain classes of immunoglobulins use to damage or kill target cells and organisms. Interestingly in the, now famous, Barnett and Prineus lesion immunoglubluin deposition was seen without the classic T cell infiltrates. Many of us now consider this to be the earliest relapse-causing lesion and based on the observations in these lesions immunoglobulins seem to be is very important inflammatory mediators.

5. B cells are the cells were EBV, the virus that is causally linked to MS, resides.

"Could the B cell be the Trojan horse that takes EBV into the brain and spinal cord? Unfortunately, the evidence on this topic is rather mixed at present, but I suspect the B-cell is the cell that EBV hitches a ride in."

6. Most if not all highly effective MS DMTs target B cells.

"This is an observation that I made several years ago! The one exception is daclizumab and working out how this drug works in MS will be very important."

7. Targeted anti-B cell therapies (anti-CD20 - rituximab, ocrelizumab, ofatumumab) are among the most promising emerging MS therapies. There superior efficacy was not expected given the current dogma that MS is T-cell driven disease.

"It is a pity that anti-CD20 therapies do not target plasma cells or plasmablasts; these are the immunoglobulin factory cells and are also part of immunoglobulin pathway. May be the newer anti-CD19 agents that target plasma blasts will be more effective than anti-CD20? Or we may have to add-on agents that target plasma cells. Plasma cells are long-lived and may therefore be the driver of progressive MS despite other upstream, adaptive, immune responses being switched off."

The Grand Challenge: "Are B cells the pivotal cell in the pathogenesis of MS? How do anti-B cell therapies work in MS? Do anti-B cell therapies work as anti-EBV agents? Are long-lived plasma cells drivers of the non-relapsing progressive phase of the disease? Will drugs targeting plasma cell biology be effective in MS?"


O Plasma-cell, Plasma-cell, wherefore art thou Plasma-cell? Deny thy father and refuse thy name; or if thou wilt not, be but sworn my love and I'll no longer be a T-cell. Shall I hear more, or shall I speak at this? 'Tis but thy name that is my enemy: thou art thyself, though not a B-cell.

CoI: multiple

16 comments:

  1. Prof G,

    The Grand Challenge: "Are B cells the pivotal cell in the pathogenesis of MS? How do anti-B cell therapies work in MS? Do anti-B cell therapies work as anti-EBV agents? Are long-lived plasma cells drivers of the non-relapsing progressive phase of the disease? Will drugs targeting plasma cell biology be effective in MS?"

    Surely the issue is setting out a programme of work and timetable to answer these questions. I wouldn't want the same questions to be listed again in five years time. ECTRIMS 2017 should focus purely on these questions. MS research has become a industry and should be refocussed on key questions such as these. Some real collaboration between research centres should answers these questions.

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  2. And at present, instead of targetting EBV, it's a case of obliterating B-cells - which are certainly useful for other things. Looking at it like that, drugs like Ocrelizumab don't look very clever.

    It reminds me in a way of what Anatoly Ivanchenko, who worked at Chernobyl right until the bitter end, was quoted as saying of nuclear power: "It's a clever hat, worn by a stupid head."

    But in the case of such drugs, they seem a stupid hat for a clever head.

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  3. Although it is clear that daclizumab increases NK. Why is daclizumab not an anti T cell agent given that it blocks IL-2 induced activation?

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    Replies
    1. Re: " Why is daclizumab not an anti T cell agent given that it blocks IL-2 induced activation?"

      It doesn't block IL-2 induced activation, it simply down regulates it from the high to intermediate affinity receptor. Patients on daclizumab still mount T-cell responses, albeit more slowly.

      Delete
    2. good question i would like to give it a whirl in eae as idea supporting original used to inhibit T cells but when t regs came along it apparently makes everything worse or does it not in ms apparently

      Delete
  4. Is there anything to stop you prescribing an anti plasma cell drug off-label?

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  5. "4. Pathological studies show immunoglobulin deposits in the brains of MSers and associated complement activation."
    This may be critically important. A recent paper posted on this blog, which reported the results of a failed (terminated early) trial of Iv and/or intrathecal rituximab in progressive MS, noted that this CD-20 binding antibody was present in the CNS (although in decreasing amounts, as it was migrated back into the blood stream), but no cell killing ensued, presumably due to the lack of complement activation.
    Where is the complement in early MS lesions coming from?

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    Replies
    1. Re: "Where is the complement in early MS lesions coming from?"

      Glial cells, in particular microglia, make complement.

      Delete
    2. Thank you.
      This is why I like this blog - a quick answer to a question, which saves me lots of time should I started searching for the answer myself (I am not a biologist).

      Delete
  6. "OCB-negative MSers don't have 'classic MS' and if I had my way they would be given a separate diagnosis.."

    What diagnosis would you make?

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    Replies
    1. Interestingly CSF-ve or OCB-ve PPMSers were not allowed into the fingolimod nor ocrelizumab PPMS trials. Pharma is already treating OCB-ve PPMS as a different disease.

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    2. I am OCB- and had an extremely intense attack that left me in the hospital for a month. After seizures, losing the ability to walk for 3 months and permanent urinary retention my doc has run out of ideas of what it could be other than MS because of persistent relapses (Double vision).

      I've only had one lesion in the pons which resolved on follow up scans.

      I personally think it is relapsing ADEM but there is no way to distinguish this from MS. Maybe this is what OCB- MS is.

      Delete
  7. If OCBs are so critical to MS pathology why are they seen in other diseases? Could it be they are just a marker of CNS cell damage in general, what ever the cause?

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    Replies
    1. Exactly:
      "Antigen-specific immune reactions to ischemic stroke"
      http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162361/

      Delete
  8. What is the current research saying about treating OCB-negative MS? Without the presence of OCBs does that mean that it isn't the B-cells doing the damage? If so is it then better to target the T-cells than B-cells with DMT's? Is there any clinical data out there when it comes to DMT's efficacy with OCB-negative MS? I haven't had much success researching DMT's in OCB negative MS.

    ReplyDelete

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