Modulation of dendritic cell properties by laquinimod as a mechanism for modulating multiple sclerosis

Abstract

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 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.

B Cell Receptor Recognition of Glatiramer Acetate is Required for Efficacy through Antigen Presentation and Cytokine Production

“…Sub-optimal responders to Copaxonemay greatly benefit from safe synergistic combination therapies such as Laquinimod. Currently in clinical trials for MS, Laquinimod has been reported to result in similar effects of GA including altering dendritic cells, inducing type II monocytes, increasing T and B regulatory cells, decreasing antigen presentation, and direct neuroprotective effects [104][105][106][107][108][109][110][111][112][113][114][115][116][117]. The novelty of this study is that a direct functional effect of GA on B lymphocytes has not been previously reported.…”

Role and therapeutic value of dendritic cells in central nervous system autoimmunity

“…[83][84][85][86] Among other effects, Laquinimod has been shown to modulate the T-cell response in rodents and humans as a result of its effects on signal transducer and activator of transcription 1 (STAT1), mitogen-activated protein kinase and NF-kB signaling in DCs. 87,88 Thus, by modulating DC function, Laquinimod might alter the balance between effector and regulatory T cells and therefore suppress the pathogenic T-cell response that drives RRMS.…”

Efficacy and safety of laquinimod in multiple sclerosis: current status

“…The exact mechanism of action of LAQ is not fully elucidated, although based on animal models LAQ has been suggested to reduce leukocyte migration into the CNS by downregulation of VLA-4-mediated adhesiveness, inhibiting Th17-proinflammatory responses and also by modulating the cytokine balance in favour of Th2/Th3 cytokines interleukin (IL)-4, IL-10 and transforming growth factor (TGF)-β [Wegner et al 2010;Yang et al 2004;Zou et al 2002;Aharoni et al 2012;Jolivel et al 2013]. In vitro experiments on human B cells from healthy or MS patients have shown that LAQ modulates B-cell activity, probably by promoting an IL10+ CD86+ CD25+ B-cell subset with regulatory features, along with other immunomodulatory mechanisms such as modulation of B-cell cytokine production and B-cell-mediated T-cell cytokine profile [Toubi et al 2012].…”

“…Treatment with LAQ of mature DCs results in reduced production of chemokines with a consequent impact on the migratory properties of monocytes [Jolivel et al 2013]. In vivo LAQ treatment modulates subpopulations of myeloid antigen-presenting cells (APC), including a decrease in DCs and an elevation of anti-inflammatory type II monocytes [Schulze-Topphoff et al 2012].…”

“…These effects were interpreted as a purely central mechanism of LAQ, mediated by downregulation of astrocyte pro-inflammatory response. Several experimental studies converge on the hypothesis that the biological effects of the LAQ are mainly mediated via inhibition of NF-κB pathway [Gurevich et al 2010;Brück et al 2012;Jolivel et al 2013].…”