Laquinimod suppress antigen presentation in relapsing–remitting multiple sclerosis: In-vitro high-throughput gene expression study

Gurevich, Michael; Gritzman, T.; Orbach, Rotem; Tuller, Tamir; Feldman, Andrew B.; Achiron, Asaf

doi:10.1016/j.jneuroim.2010.02.010

Cited by 64 publications

(59 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…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: 98%

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

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 98%

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

View full text Add to dashboard Cite

show abstract

“…24,25 Although the exact mechanism(s) of action of laquinimod is/are incompletely understood, this drug has been reported to (a) decrease secretion of proinflammatory cytokines and enhance secretion of antiinflammatory cytokines and (b) upregulate brainderived neurotrophic factor. 26,27 In addition, laquinimod was shown in an in vitro study to suppress genes associated with antigen presentation and inflammation in peripheral blood mononuclear cells from both healthy controls and patients with relapsing MS. 28 Laquinimod has been evaluated in 2 large, randomized phase 3 studies known as ALLEGRO (Assessment of oraL Laquinimod in prEventing proGRession Of MS; NCT00509145), which has a placebo control arm, and BRAVO (Benefit-Risk Assessment of Avonex and Laquinimod; NCT00605215), in which the active comparator is IFNβ-1a 30 mcg per week. Neither the results from BRAVO nor ALLEGRO have been published in the peer-reviewed literature.…”

Section: Managed Approaches To Multiple Sclerosis In Special Populationsmentioning

confidence: 99%

Managed Approaches to Multiple Sclerosis in Special Populations

Sperandeo¹,

Nogrady²,

Moreo³

et al. 2011

JMCP

View full text Add to dashboard Cite

“…23 In vitro study of peripheral blood cell subtypes in RRMS patients has also shown activation of the anti-inflammatory IL-4 pathway in CD4+ cells, a decrease in genes involved in CD8+ proliferation, including the critical E2F3-transcription factor, and suppression of metabolic activity of CD14+ and natural killer cells. Additionally, laquinimod may reduce the accumulation of monocytoid cells in the human central nervous system through reduced levels of cytokines, matrix metalloproteinase-9, and beta2-integrins.…”

Section: Mechanism Of Actionmentioning

confidence: 99%

Profile of oral laquinimod and its potential in the treatment of multiple sclerosis

West¹,

Miravalle²

2011

DNND

View full text Add to dashboard Cite

Abstract:The medications available to treat relapsing-remitting multiple sclerosis (RRMS) are expanding as newer, and more potent, disease-modifying treatments become available. In particular, there is an impetus for safe and effective oral options. Laquinimod is a novel oral immunomodulator currently under investigation for the treatment of RRMS. Although the exact mechanism of action is not known, laquinimod is not an immunosuppressant. Rather, it appears to have multiple effects on the immune system, including a shift to an anti-inflammatory cytokine state, reduction in antigen presentation, and effect on migration of T cells. In addition, laquinimod may have a neuroprotective effect. Phase II trials of RRMS patients showed a statistically significant reduction in magnetic resonance imaging (MRI) outcomes, such as decrease in gadolinium-enhancing lesions, and initial Phase III data have now shown a reduction in relapse rate, reduction in sustained disability, and a decrease in atrophy on brain MRI. In all trials, laquinimod has shown a favorable tolerability and safety profile. Laquinimod has been granted fast-track status by the US Food and Drug Administration, and may become an approved treatment for RRMS.

show abstract

Laquinimod suppress antigen presentation in relapsing–remitting multiple sclerosis: In-vitro high-throughput gene expression study

Cited by 64 publications

References 63 publications

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

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

Managed Approaches to Multiple Sclerosis in Special Populations

Profile of oral laquinimod and its potential in the treatment of multiple sclerosis

Contact Info

Product

Resources

About