Natural killers cells and the action of daclizumab

Have we found a handle on the viral cause of MS? #MSBlog #MSResearch

"As most of you are aware of my pent up excitement about daclizumab as a treatment for RRMS. I have several reasons for taking this position. Firstly, it is a highly effective treatment that is superior to interferon-beta and has an impact on end-organ damage, i.e. it is one of an emerging group of high-efficacy therapies that reduces brain volume loss or brain atrophy. However, I am most excited by daclizumab as it seems to be an outlier when it comes to its mode of action. All the other high-efficacy therapies have in common some effect on the B-cell (natalizumab, fingolimod, alemtuzumab, mitoxantrone, anti-CD20 & HSCT/BMT). In comparison, daclizumab appears to leave the B-cell compartment intact and its efficacy is linked, at least in part, to expansion of natural killer cells (NK-cells) that express a molecule on their surface called CD56. What is the function of NK cells? They are part of the innate immune system and are anti-viral and part of the immune surveillance system for malignancies. Could the NK-cell be a one of the clues that MS is due to a virus? Personally, I think yes which is why I always include daclizumab on my storyboard when I discuss the hypothesis that MS is due to a virus. What are we doing about this? We as a group have therefore launched the Charcot Project, which is a group of projects that are looking into the viral hypothesis of MS."

"The study below confirms that the expansion of the NK cell population is linked to the effectiveness of daclizumab. However, in the group of MSers with the lowest level of expansion of the NK-cells daclizumab is still effective, albeit at a lower level."

"Daclizumab also challenges the immunological dogma that MS is an autoimmune disease. A large number of immunologists have claimed that MS is due to a problem with T-reg cells. Daclizumab actually reduces the number of T-regs in the peripheral blood. The reduction in T-reg numbers may explain why some daclizumab-treated MSers get other autoimmune diseases (skin, liver and gut) as a complication of daclizumab-treatment. What daclizumab maybe telling us is that MS is not an autoimmune disease? Interestingly, Professor David Hafler in his ACTRIMS-ECTRIMS lecture made the claim that we have now proven that MS is an autoimmune disease did not mention, or discuss daclizumab, once in his lecture."

'The great tragedy of Science — the slaying of a beautiful hypothesis by an ugly fact'. Thomas Henry Huxley (4 May, 1825 – 29 June 1895) 

"Is daclizumab a black swan?"

Elkins et al. CD56(bright) natural killer cells and response to daclizumab HYP in relapsing-remitting MS. Neurol Neuroimmunol Neuroinflamm. 2015 Jan 22;2(2):e65. doi: 10.1212/NXI.0000000000000065.

OBJECTIVE: To assess the relationship between CD56(bright) natural killer (NK) cells and MS disease activity in RRMSers treated with daclizumab high-yield process (DAC HYP).

METHODS: Data were from MSers enrolled in a 52-week randomized, double-blind, placebo-controlled study of DAC HYP and its extension study. Assessments included relationships of CD56(bright) NK cell numbers (identified using fluorescence-activated cell sorting) at weeks 4 and 8 with the numbers of new or newly enlarging T2-hyperintense lesions between weeks 24 and 52 and the annualized relapse rate.

RESULTS: In DAC HYP-treated MSers but not placebo-treated MSers, the numbers of CD56(bright) NK cells increased over 52 weeks of treatment, and their numbers at weeks 4 and 8 predicted the number of new or newly enlarging T2-hyperintense lesions between weeks 24 and 52 of treatment (p ≤ 0.005 for each comparison). Similar but non-significant trends were observed between CD56(bright) NK cell counts and the annualized relapse rate in DAC HYP-treated MSers. DAC HYP-treated MSers who showed lower levels of expansion of CD56(bright) NK cells still developed fewer new or newly enlarging T2-hyperintense lesions than placebo-treated patients during the first year of treatment.

CONCLUSIONS: CD56(bright) NK cells appear to mediate some of the treatment-related effects of DAC HYP, but their numbers do not account for the full effect of DAC HYP on MS-related outcomes.

CoI: multiple, I am also a co-author on this paper

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