Thursday, 20 November 2014

Tysabri affects B cells

Warnke C, Stettner M, Lehmensiek V, Dehmel T, Mausberg AK, von Geldern G, Gold R, Kümpfel T, Hohlfeld R, Mäurer M, Stangel M, Straeten V, Limmroth V, Weber T, Kleinschnitz C, Wattjes MP, Svenningsson A, Olsson T, Hartung HP, Hermsen D, Tumani H, Adams O, Kieseier BC. Natalizumab exerts a suppressive effect on surrogates of B cell function in blood and CSF. Mult Scler. 2014 Nov 12. pii: 1352458514556296. [Epub ahead of print]

BACKGROUND:Natalizumab for multiple sclerosis (MS) increases the risk of progressive multifocal leukoencephalopathy (PML).
OBJECTIVE:We aimed to assess the effect of natalizumab on cellular composition and functional B cell parameters including patients with natalizumab-associated PML (n=37).
METHODS: Cellular composition by flow cytometry, levels of immunoglobulin (Ig)G/IgM by immunonephelometry, and oligoclonal bands by isoelectric focusing were studied in blood and cerebrospinal fluid.
RESULTS:In MS patients treated with natalizumab without PML (n=59) the proportion of CD19+ B cells was higher in blood, but lower in cerebrospinal fluid compared with MS patients not treated with natalizumab (n=17). The CD4/CD8-ratio in cerebrospinal fluid was lower, and IgG and IgM levels as well as the IgG index dropped in longitudinal samples during natalizumab therapy. Oligoclonal bands persisted, but the total amount of the intrathecally produced IgG fraction, and the polyclonal intrathecal IgG reactivity to measles, rubella, and zoster declined. At the time of diagnosis of PML patients with natalizumab-associated PML had low total IgG levels in blood and cerebrospinal fluid.
CONCLUSIONS:Natalizumab impacts B and T cell distribution and exerts an inhibitory effect on surrogates of B cell function in periphery and in cerebrospinal fluid, potentially contributing to the increased risk of developing PML.


EAE has given us the T cell as he target for MS, however one may argue that T cell -immunotherapy has yet to inhibit relapsing MS and most immunotherapeutics that affect MS inhibit B cell function. This study looks at B cell function. Natalizumab blocks white cell migration into the CNS and in people taking the drugs that B cell seems to get stuck in the blood and there were fewer B cells in the CNS and the amounts of antibody, including anti-viral drugs dropped in the CSF. So could suggest that B cells are not necessarily generated within the CNS, from B cell follicles but come from the blood. Another possibility could be that T cells coming from the blood are blocked and so the growth factors used by B cells for making antibodies are blocked.

ProfG may argue that the reason these drugs work is because they  block B cells that carry the virus that drives MS. However, do T cells play no role in susceptibility to MS. The genetics say that MHC class II is the major susceptibility function in MS, so why did depletion of T cells not impact in MS? Either Tcells are not important or most likely the trials were fundementally flawed and the level of depletion was not enough.

8 comments:

  1. More and more cues that MS might be a B cell driven condition !

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    1. Then why anti-cd20's does not look like to be an induction therapy, but BMT and alemtuzumab does?

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    2. Careful, we'll have the T cell disciples creating a fuss with that kind of talk!

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  2. its not clear yet , anti-CD20 might be an induction therapy .. can't wait till OPERA study results are out !

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    1. Yes, there is no results yet... only anecdotal reports. But all trial participants in the local community report that disease comes back in 1-1.5 years. And there are some commenters in this blog who said the same thing

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    2. Personal experience which may not be typical: re-dosing is needed at 6 months.
      This seems to be a norm with RA too

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  3. Let's wait and see , unlocking the secrets of MS pathogenisis is key to finding a safe and effective cure

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  4. Less lymphocyte trafficking into CNS due to natalizumab dampens the inflammatory environment of the CNS as a result the BBB is less permeable. Lymphocytes are responding to pathogen/endogenously expressed antigen inside the CNS. What might this be? I'll buy the autoimmune hypothesis when there's an auto-antigen identified, EAE induction is not MS.

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