Thursday, 20 December 2012

Research: CD4 T cell recovery after Alemtuzumab predicts disease return



OBJECTIVEAlemtuzumab is potentially a highly effective treatment for relapsing multiple sclerosis (MS) acting via complement-mediated lysis of circulating lymphocytes. Variability in post-treatment lymphocyte recovery time is observed, with some patients showing striking durability in the efficacy of treatment. This study aims to establish whether this observed variation affects clinical and imaging parameters of disease activity.

METHODSA total of 56 patients were followed for a median of 39.5 months post alemtuzumab treatment with interval clinical assessments, lymphocyte immunophenotyping, and MRI. Timing and degree of CD4+, CD8+ (T cell), and CD19+ (B cell) recovery were correlated with the re-emergence of disease activity defined as clinical relapse, increasing disability, and new T2/enhancing lesions on MRI.

RESULTSNew disease activity was recorded in 14% of patients. Mean time to CD19+, CD8+, and CD4+ reconstitution was 6, 10, and 36 months. No differences were observed in CD8+ and CD19+ reconstitution between patients with active disease and those in remission. Patients with active disease showed an accelerated recovery of CD4+ cells (p = 0.001) with a difference in absolute CD4+ counts at 24 months (p = 0.009). CD4+ counts <388.5 × 10(6) cells/mL predicted MRI stability.

CONCLUSIONSDifferential lymphocyte recovery in MS following alemtuzumab may be a biomarker for relapse and also inform monitoring and treatment protocols.


There is not much hard evidence to implicate CD4+ T cells as drivers of MS, yet it is clear that they are drivers in autoimmune diseases in all animal models. This study suggests that when CD4 T cell counts return after depletion with Alemtuzumab, disease can become active again.

The CD4 antibody trial was in my opinion an example of a messed up trial....but they did not deplete aggressively at that time because AIDS had just arrived and there was a worry about taken white blood cells below 200 cells per microlitre. This level of depletion in the CD4 antibody Trial was insignificant compared to that induced by Alemtuzumab and even in EAE this level of depletion was not enough to stop disease. Furthermore, the CD4 antibody used did not deplete memory T cells that well so was perhaps doomed before it started.

This CD4 Trial was led by a Young Prof Miller from UCLP. Remember to come see the Older Prof Miller at the Research Day as he is another of those famous Neuros from UCLP coming to talk with you.

19 comments:

  1. So much for alemtuzumab being a cure for MS? Another false hope!

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    1. Just means you need to re-treat if disease comes back and it only comes back in some patients. Alemtuzumab is merely a step on the way to an eventual cure. The next step should be to selectively remove/inactivate the cells causing lesions whilst leaving the rest of the immune system intact. We can do this in our mice and it needs to be taken on in patients.

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    2. I thought the new cells after repopulation wont cause any
      damage

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    3. It is probably disease causing cells that werent depleted enough and regulation

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  2. MouseDoc, Campath is gone; it is dead and buried. I believe the new,supercharged version of alemtuzumab, is being called Lemtrada. The rebranding will obviously come with a hefty price tag. How much will it cost? This is the really million, or should I say, billion dollar question?

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    1. If you dress a banana in a pea pod it is still a banana the active ingredient in lemtrada is campath. It is. Jist less campath than in alemtuzumab. So perfect sense dress a drug up in a new package and make more money out of supplying less....not..
      The cost you can be sure it will be alot.
      We need a generic to break this spiral

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  3. Will Cambridge still get royalties on Lemtrada? If yes, it will be in their interest for the drug to sell billions would it not?

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    1. They've already received a bung of a few million from Genzyme. No doubt more to follow.

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    2. $6,000,0000 was one donation: http://www.neuroscience.cam.ac.uk/news/article.php?permalink=fa17475030.

      No wonder the drug is going to cost so much!

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    3. Wonder how much gets funneled to ms research

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  4. Alem is supposed to deplete B-cells. Yet, the disease exacerbated when CD4+ T-cells reconstituted. Moreover "There is not much hard evidence to implicate CD4+ T cells as drivers of MS". Isn't this evidence against EBV and in favour of an unknown disease process to which the immune activity is just a normal response?

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  5. Alem does deplete B cells, CD19 is B cells and they recover quicker than T cells and this may be the problem as they seem to overshoot, maybe this is why B cell autoimmunities surface.

    Is this evidence...don't see why

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  6. "CD19 is B cells and they recover quicker than T cells"

    Then how do you explain this:
    "No differences were observed in CD8+ and CD19+ reconstitution between patients with active disease and those in remission."

    B-cells are to blame, but not for all patients?

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    1. Who said B cells in the blood drive relapses....not me.
      However, they can be antigen presenting cells to drive T cells.

      However what happens in the CSF, does alemtuzumba get rid of B cells in the brain? I'm not sure they know this. In terms of EBV and B cell depletion after Alemtuzumab I'll let Prof G answer this if it is known, I don''t know.

      Likewise you are looking at gross populations and the important elemenets will only be a fraction of this population so can you see the trees in the wood.

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  7. Would it be possible to test for this rise in CD4 Tcells clinically and treat proactively with alem prior to a relapse occurring? If any relapse contributes to later progression, this would seem worthwhile to attempt to prevent, unless it is not a test that can be practically done?

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    1. People on alemtuzumab have to be checked monthly for risk of autoimmunities, so it would be feasible to monitor CD4 levels, this could be done within 30 minutes.

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