Tuesday, 26 March 2013

Laquinimod inhibits dendritic cell function

Epub: Jolivel et al. Modulation of dendritic cell properties by laquinimod as a mechanism for modulating multiple sclerosis. Brain. 2013 Mar 20. 

Laquinimod is an orally administered compound that is under investigation in relapsing-remitting multiple sclerosis. To understand the mechanism by which laquinimod exerts its clinical effects, we have performed human and murine (IT'S MOUSE!!!!) studies assessing its immunomodulatory properties. In experimental autoimmune encephalomyelitis, the therapeutic administration of laquinimod beginning during the recovery of SJL mice, prevented further relapses as expected and strongly reduced infiltration of CD4+ and CD8+ T cells in the central nervous system. We hypothesized that this beneficial effect was mediated by dendritic cells, since we and others found a modulation of different dendritic cell subsets under treatment. According to the findings on antigen-presenting cells in the murine system, we found a reduced capacity of human monocyte-derived dendritic cells treated with therapeutic concentrations of laquinimod, upon maturation with lipopolysaccharide, to induce CD4+ T cell proliferation and secretion of pro-inflammatory cytokines. Furthermore, laquinimod treatment of mature dendritic cells resulted in a decreased chemokine production by both murine and human dendritic cells, associated with a decreased monocyte chemo-attraction. In laquinimod-treated patients with multiple sclerosis we consistently found reduced chemokine and cytokine secretion by conventional CD1c+ dendritic cells upon lipopolysaccharide stimulation. Similarly to the animal model of relapsing-remitting multiple sclerosis, dendritic cell subsets were altered in patients upon laquinimod treatment, as the number of conventional CD1c+ and plasmacytoid CD303+ dendritic cells were decreased within peripheral blood mononuclear cells. Moreover, laquinimod treatment in patients with multiple sclerosis and mice modified the maturation of dendritic cells demonstrated by an upregulation of CD86 expression in vivo. Our data suggest that inhibition of the NF-κB pathway is responsible for the changes observed in dendritic cell maturation and functions. These findings indicate that laquinimod exhibits its disease-modulating activity in multiple sclerosis by downregulating immunogenicity of dendritic cell responses. We suggest that monitoring dendritic cell properties in multiple sclerosis should be implemented in future therapeutic trials.



It is always good to understand how a drug works. This study reports that laquinimod affects dendritic cell function. Dendritic cells are specialized immune cell that is very good at inducing immune responses in T cells. In this study laquinimod inhibited relapses and therefore it would stop accumulation of immune cells into the CNS and in mice and humans there was a reduction in dendritic cell function. However we have to remember that in trials laquinimod did worse than beta interferon at slowing relapses. So what is the significance of these observations? Could this be more important in progression and explain why laquinimod seemed to slow brain shrinkage, much better than it stopped relapses.

3 comments:

  1. Interesting to see Novartis shifting their focus from relapses to brain atrophy

    " Brain volume loss is the best magnetic resonance imaging (MRI) correlate of long-term disability. "

    http://www.novartis.com/newsroom/media-releases/en/2013/1688111.shtml

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  2. What we want is Sir Jeremy to complete further research on Simvastatin as it seemed to be effective in slowing brain volume loss - I for one would like to be able to take it at the necessary dose, as I did on the trial with no ill effects.

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  3. Yes we would like to see more studies so that simvastatin is available for those that it would be of benefit, but it has been thought through!

    Who is going to to support the phase III study? and who is going to suport the licensing application that may cost a few hundred thousand/million.?

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