Modulation of Autoimmune Demyelination by Laquinimod via Induction of Brain-Derived Neurotrophic Factor

Thöne, Jan; Ellrichmann, Gisa; Seubert, Silvia; Peruga, Isabella; Lee, De Hyung; Conrad, Rebecca; Hayardeny, Liat; Comı, Gıancarlo; Wiese, Stefan; Linker, Ralf A.; Gold, Ralf

doi:10.1016/j.ajpath.2011.09.037

Cited by 130 publications

(125 citation statements)

References 30 publications

(32 reference statements)

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“…The influence of laquinimod on the immune system was studied in experimental autoimmune encephalomyelitis (EAE) (4)(5)(6)(7)(8)(9)(10)(11)(12), an autoimmune disease mediated by proinflammatory myelinreactive lymphocytes that cause CNS inflammation leading to demyelination and axonal loss. Laquinimod has also been effective in the treatment of other models of autoimmune diseases, specifically experimental autoimmune neuritis (13,14), lupus nephritis (15), and colitis (16).…”

mentioning

confidence: 99%

Laquinimod arrests experimental autoimmune encephalomyelitis by activating the aryl hydrocarbon receptor

Kaye

Piryatinsky

Birnberg

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

112

102

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Laquinimod is an oral drug currently being evaluated for the treatment of relapsing, remitting, and primary progressive multiple sclerosis and Huntington's disease. Laquinimod exerts beneficial activities on both the peripheral immune system and the CNS with distinctive changes in CNS resident cell populations, especially astrocytes and microglia. Analysis of genome-wide expression data revealed activation of the aryl hydrocarbon receptor (AhR) pathway in laquinimod-treated mice. The AhR pathway modulates the differentiation and function of several cell populations, many of which play an important role in neuroinflammation. We therefore tested the consequences of AhR activation in myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) using AhR knockout mice. We demonstrate that the pronounced effect of laquinimod on clinical score, CNS inflammation, and demyelination in EAE was abolished in AhR −/− mice. Furthermore, using bone marrow chimeras we show that deletion of AhR in the immune system fully abrogates, whereas deletion within the CNS partially abrogates the effect of laquinimod in EAE. These data strongly support the idea that AhR is necessary for the efficacy of laquinimod in EAE and that laquinimod may represent a first-in-class drug targeting AhR for the treatment of multiple sclerosis and other neurodegenerative diseases.aryl hydrocarbon receptor | EAE | laquinimod L aquinimod is an oral drug that is currently in late-stage clinical development for the treatment of relapsing remitting multiple sclerosis (RRMS), primary progressive MS, and Huntington's disease. Current knowledge indicates that laquinimod exerts activities both on the peripheral immune system and within the CNS. Laquinimod, at the 0.6-mg/d dose, has demonstrated efficacy in phase II and III MS clinical trials, in which it reduced relapse rate, disability progression, development of new and active MRI lesions, and brain atrophy (1-3). The clinical efficacy profile of laquinimod is characterized by a dissociation of the moderate magnitude of the effect on relapse reduction and its associated inflammatory MRI findings and the disproportionally large effect on disability progression. Such an efficacy profile in patients with RRMS may relate to a distinctive intracerebral activity potentially mediated via changes in CNS resident cell populations, potentially astrocytes and microglia.

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mentioning

confidence: 99%

Laquinimod arrests experimental autoimmune encephalomyelitis by activating the aryl hydrocarbon receptor

Kaye

Piryatinsky

Birnberg

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

112

102

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“…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.…”

Section: Discussionmentioning

confidence: 82%

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

Jackson

Selva²,

Niedzielko³

et al. 2014

J Clin Cell Immunol

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Multiple Sclerosis (MS) is a chronic inflammatory disorder of the central nervous system (CNS) leading to neuronal demyelination, lack of remyelination, and axonal loss. If left untreated, patients inevitably suffer from severe cognitive, psychological and physical disabilities.Although not yet approved, B cell depletion achieved with anti-CD20 monoclonal antibodies is the most effective therapy to-date in MS patients. As this therapeutic depletes immune cells potentially important in pathogen immunity, an immense need remains for highly efficacious therapeutics maintaining a favorable safety profile. Even amongst the emergence of new therapeutic options for patients with MS, the myelin basic protein mimetic, Copaxone (glatiramer acetate, GA), remains the most commonly prescribed drug in the United States. As specific B cell depletion appears to be the most effective therapy for MS patients, the goal of this study was to further elucidate the mechanism of action of GA on B lymphocytes. Our studies show that GA directly interacts with human and murine B cell receptors (BCR) inducing the activation of B lymphocytes and BCR recognition of GA is required for efficacy in an animal model of MS. GA loaded B lymphocytes resulted in IL-2 production from CD4 + T cells suggesting B lymphocytes serve as an antigen presentation source for GA. In fifty-percent of the MS patients tested, GA stimulation reduced baseline levels of the pro-inflammatory cytokines IL-6 and TNFα in purified B lymphocytes, while other cytokines were not consistently altered. Taken together, this data suggests that the mechanism of action of GA on B lymphocytes includes the presentation of GA to T lymphocytes in the context of an anti-inflammatory cytokine milieu. The results from this study provide a strong foundation for future exploration of optimal Copaxone responders or synergistic combination therapies with an improved risk: benefit ratio compared to currently approved therapeutics for MS.

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“…Axonal protection by LAQ was also observed in a rat model of optic neuritis [Sühs, 2007]. Also in patients with MS, LAQ treatment results in a significant and persistent increase in BDNF serum levels when compared with baseline and placebo-treated patients [Thöne et al 2012]. Furthermore, it was demonstrated that the attenuation of EAE by LAQ to be mediated by the reduction of overactive NMDA receptors of presynaptic terminal, while increasing GABAergic synaptic currents.…”

Section: Introductionmentioning

confidence: 94%

“…Recently it has been suggested that the beneficial effect of LAQ may be mediated by modulation of dendritic cells (DCs) affecting the antigen presentation capacity [Gurevich et al 2010;Thöne et al 2012;Jolivel et al 2013]. Under treatment with LAQ, both in murine models and in patients with MS, a reduction in the number of DCs has been observed, in addition to a reduced ability of these cells to induce the proliferation of CD4 + T cells as well as to stimulate the secretion of proinflammatory cytokines [Jolivel et al 2013].…”

Section: Introductionmentioning

confidence: 99%

Efficacy and safety of laquinimod in multiple sclerosis: current status

Haggiag

Ruggieri

Gasperini

2013

Ther Adv Neurol Disord

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Laquinimod is a novel immunomodulatory agent, in development as a potential disease-modifying treatment for multiple sclerosis (MS). Structurally related to linomide, its pharmacological predecessor, laquinimod combines anti-inflammatory and possibly clinically relevant neuroprotective effects with the convenience of oral administration. In this review we aim to highlight the immunomodulatory and neuroprotective effects of laquinimod, and to describe its effects in animal models of MS. Furthermore, we focus on current results of clinical studies in MS. Randomized, controlled clinical trials in relapsing MS demonstrate a dose-response effect on disease activity, measured by reduced clinical relapse rate, reduced number of brain MRI active lesions, as well as on sustained disability and brain atrophy. Laquinimod has a favourable tolerability and safety profile. A new phase III study, recently completed, will soon provide further details on the therapeutic potential of this drug. Laquinimod is a promising emerging treatment for relapsing-remitting MS that may provide a new therapeutic option in the near future.

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Modulation of Autoimmune Demyelination by Laquinimod via Induction of Brain-Derived Neurotrophic Factor

Cited by 130 publications

References 30 publications

Laquinimod arrests experimental autoimmune encephalomyelitis by activating the aryl hydrocarbon receptor

Laquinimod arrests experimental autoimmune encephalomyelitis by activating the aryl hydrocarbon receptor

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

Efficacy and safety of laquinimod in multiple sclerosis: current status

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