Tuesday, 22 October 2013

Alemtuzumab may prolong T reg function

Havari E, Turner MJ, Campos-Rivera J, Shankara S, Nguyenz TH, Roberts B, Siders W, Kaplan JM. Impact of alemtuzumab treatment on the survival and function of human regulatory T cells in vitro. Immunology. 2013 Oct 5. doi: 10.1111/imm.12178. [Epub ahead of print]


Alemtuzumab is a humanized monoclonal antibody specific for the CD52 protein present at high levels on the surface of B and T lymphocytes. In clinical trials, alemtuzumab has shown a clinical benefit superior to that of interferon beta in relapsing-remitting multiple sclerosis (RRMS) patients. Treatment with alemtuzumab leads to the depletion of circulating lymphocytes followed by a repopulation process characterized by alterations in the number, proportions and properties of lymphocyte subsets. Of particular interest, an increase in the percentage of T cells with a regulatory phenotype (Tregs) has been observed in MS patients post-alemtuzumab. Since Tregs play an important role in the control of autoimmune responses, the effect of alemtuzumab on Tregs was further studied in vitro. Alemtuzumab effectively mediated complement-dependent cytolysis (CDC) of human T lymphocytes and the remaining population was enriched in T cells with a regulatory phenotype. The alemtuzumab-exposed T cells displayed functional regulatory characteristics including anergy to stimulation with allogeneic dendritic cells and ability to suppress the allogeneic response of autologous T cells. Consistent with the observed increase in Treg frequency, the CD25hi T cell population was necessary for the suppressive activity of alemtuzumab-exposed T cells. The mechanism of this suppression was found to be dependent on both cell-cell contact and IL-2 consumption. These findings suggest that an alemtuzumab-mediated increase in the proportion of Tregs may play a role in promoting the long term efficacy of alemtuzumab in MS patients.
Tregs are immunological flavour of the month and this study suggests that Lemtrada may help by promoting T regulatory cell 
function, thought to limit the generation of autoimmunity, in addition to causing long-term depletion of other white blood cells. These may help stop MS return but one could also ask why then to MSers get secondary autoimmunities as a consequence of alemtuzumab?

8 comments:

  1. Good for people that can access this drug, which is... nobody?

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  2. "These may help stop MS return but one could also ask why then to MSers get secondary autoimmunities as a consequence of alemtuzumab?"

    Yapp, this is a good question.

    But it raises some other questions too.

    1. IS MS a "classic" autoimmune disorder?
    2. does MS work on a different level than Thyreoiditis?
    3. does Alemtuzumab block an important "communiaction pathway" which may help MSers but in addition gifts you with another disease (likely in my opinion)?

    When I got it right the developers of MabCampath are very confident that they can stop the secondary disorders with an additional drug while on Alemtuzumab (I wonder if that could be iodinde in the case of Thyreoiditis).

    But how to predict if you get a thyroid hyper or hypofunction?

    Still Almtuzumab would be the drug of my choice for future treatments when I run out of my lifetime dose of Mitoxantrone.

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  3. The problem with immune depletion therapy like Alemtuzumab and even HSCT is that it takes a while for CD4+ tcells to recover, and they never come back fully to baseline values. Since Tregs are CD4+ Tcells, you are vulnerable during this period of recover. Yes, you diminish the autoreactive Tcells during the therapy, but the long Plasma cells still survive:

    "Plasma cells can survive vigorous lymphodepletion by HSCT,15 if regulatory cells, controlling these autoreactive plasma cells are suppressed by conditioning; clinically significant manifestations of autoimmunity may develop.16 De novo emergence of autoreactive B or T cells after HSCT may also contribute to autoimmunity in these patients."

    http://bloodjournal.hematologylibrary.org/content/118/6/1693.full.html

    I think it is time to acknowledge that Tregs are real and join the rest of the established scientific community.

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    Replies
    1. Maybe Dr Coles can shed some light I remember he had some similar work as on the value of Tregs and Alemtuzumab.

      I think T regs are real

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    2. I think T regs are real too, just not the universal panacea for everything to do with MS.

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  4. Why do MSers get secondary autoimmunity as a consequence of alemtuzumab therapy? The protective effect of Tregs and induction of tolerance is a fine line during immune re-population. HIVers also are prone to autoimmunity following induction of HAART and increase in Th17. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2886291/pdf/nihms203437.pdf
    Increase in incidence of secondary autoimmunity following HSCT therapy.http://bloodjournal.hematologylibrary.org/content/109/6/2643.full.html

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    Replies
    1. Why do you get B cell Autoimmunity.

      ProfG thinks it may have something to do with the B cell overshoot that happens when B cells repopulate and go above their normal levels.

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    2. It is a easy testable hypothesis just get rid of the B cells and see if it delays, removes the antibody driven autoimmunity

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