Wednesday, 3 June 2015

Daclizumab inhibits accumulation of cells in the CNS

Lin YC, Winokur P, Blake A, Wu T, Romm E, Bielekova B.
Daclizumab reverses intrathecal immune cell abnormalities in multiple sclerosis.Ann Clin Transl Neurol. 2015;2:445-55

OBJECTIVE:Novel treatments such as natalizumab and fingolimod achieve their therapeutic efficacy in multiple sclerosis (MS) by blocking access of subsets of immune cells into the central nervous system, thus creating non-physiological intrathecal immunity. In contrast, daclizumab, a humanized monoclonal antibody against the alpha chain of the IL-2 receptor, has a unique mechanism of action with multiple direct effects on innate immunity. As cellular intrathecal abnormalities corresponding to MS have been well defined, we asked how daclizumab therapy affects these immunological hallmarks of the MS disease process.
METHODS:Nineteen subpopulations of immune cells were assessed in a blinded fashion in the blood and 50-fold concentrated cerebrospinal fluid (CSF) cell pellet in 32 patients with untreated relapsing-remitting MS (RRMS), 22 daclizumab-treated RRMS patients, and 11 healthy donors (HDs) using 12-colour flow cytometry.
RESULTS:Long-term daclizumab therapy normalized all immunophenotyping abnormalities differentiating untreated RRMS patients from HDs. Specifically, strong enrichment of adaptive immune cells (CD4+ and CD8+ T cells and B cells) in the CSF was reversed. Similarly, daclizumab controlled MS-related increases in the innate lymphoid cells (ILCs) and lymphoid tissue inducer cells in the blood and CSF, and reverted the diminished proportion of intrathecal monocytes. The only marker that distinguished daclizumab-treated MS patients from HDs was the expansion of immunoregulatory CD56(bright) NK cells.
INTERPRETATION:Normalization of immunological abnormalities associated with MS by long-term daclizumab therapy suggests that this drug's effects on ILCs, NK cells, and dendritic cell-mediated antigen presentation to CD4+ and CD8+ T cells are critical in regulating the MS disease process.

How does daclizumab work.....The other DMT wipe out B cells, which may be the home of EBV. In contrast daclizumab augments natural killer cell activity, does that mean it has anti-microbe activity? Others says that the DMT affect T cell function and daclizumab could affect T cell function but also antigen presenting cell function. However, it appears to limit either the accumulation of cells within the CNS or controls the cells within the CNS so that fewer are found in the spinal fluid. This is a central hallmark of effective DMT,which is to limit activity of immune cells in the CNS. Where is this drug going to figure in the treatment of MS?

Biogen will have more different DMT that their competitors with ocreluzimab soon to follow one suspects. Is their motto escalate from one of our drugs to the next...or we don't care just buy our drugs. 

CoI: None

6 comments:

  1. If it normalises the immune system, does that out dacluzimab into the "potential cure" pot as well, alongside lemtrada?

    Where on the spectrum of efficacy does this sit versus the other drugs?

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    1. Some questions as Matt...

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    2. Good question. I dont know enough about this drug,but i think it is not an induction therapy and i dont know how long the NK cells stay high. ProfG was a PI inearly studies so will have more insider info than me. In the spectrum it is in the highly active category. How this will place in the treatment hierarchy I dont know, it depends on the side effect profile i suspect.

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  2. Well I supose that MS is driven By multiple factors and that is the reason why some treatment are helpful at some people and some Not. I think that there exist an amount of bacterias/viruses which infiltrate the CNS binding at some proteins or lipids or use the myelin for self -reproduction or initiate some immune respone. This could explain why the complemental system is high active (neutrophilia for example in autoimmune diseases ) and why macrophages are active and why ms is from the start degenerative. Some publications suggest different bacterias to cause cns -disorders similar to eae. I hope that the cause of ms will bei identified instand of wasting money to identify genome SequencesSequences

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  3. Dacluzimab sounds more and more like a drug that could have an impact on progressive MS insofar as one theory holds that progression is driven from behind the BBB. An impact on CSF and IgG snythesis is observed with natalizumab as well. Do you agree that this drug could be huge?

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    1. it will be what it will be, its not been licensed yet. How much antibody gets into the CNS...not much I suspect

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