Dendritic cell, monocyte and T cell activation and response to glatiramer acetate in multiple sclerosis

Sellebjerg, Finn; Hesse, Dan; Limborg, Signe; Lund, Henrik Hautop; Søndergaard, Helle Bach; Krakauer, Martin; Sørensen, P. S.

doi:10.1177/1352458512450353

Cited by 31 publications

(31 citation statements)

References 29 publications

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“…Overrepresented GO terms included 'lymphocyte proliferation’ and 'regulation of T-cell proliferation’. These findings are consistent with earlier studies that showed that GA suppresses lymphocyte proliferation through modulation of monocytes and monocyte-derived dendritic cells, thereby reducing the number of autoreactive T-cells [38,62,63]. Members of these GO terms are, for example, cytokines such as IL18 and TNFSF14.…”

Section: Discussionsupporting

confidence: 92%

Glatiramer acetate treatment effects on gene expression in monocytes of multiple sclerosis patients

Thamilarasan

Hecker

Goertsches

et al. 2013

J Neuroinflammation

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BackgroundGlatiramer acetate (GA) is a mixture of synthetic peptides used in the treatment of patients with relapsing-remitting multiple sclerosis (RRMS). The aim of this study was to investigate the effects of GA therapy on the gene expression of monocytes.MethodsMonocytes were isolated from the peripheral blood of eight RRMS patients. The blood was obtained longitudinally before the start of GA therapy as well as after one day, one week, one month and two months. Gene expression was measured at the mRNA level by microarrays.ResultsMore than 400 genes were identified as up-regulated or down-regulated in the course of therapy, and we analyzed their biological functions and regulatory interactions. Many of those genes are known to regulate lymphocyte activation and proliferation, but only a subset of genes was repeatedly differentially expressed at different time points during treatment.ConclusionsOverall, the observed gene regulatory effects of GA on monocytes were modest and not stable over time. However, our study revealed several genes that are worthy of investigation in future studies on the molecular mechanisms of GA therapy.

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Section: Discussionsupporting

confidence: 92%

Glatiramer acetate treatment effects on gene expression in monocytes of multiple sclerosis patients

Thamilarasan

Hecker

Goertsches

et al. 2013

J Neuroinflammation

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“…Interestingly, this reduced expression is correlated with an improved disease course. 33 Natalizumab. Natalizumab, a monoclonal antibody directed against very late antigen (VLA)-4, prevents leukocyte infiltration in the brain.…”

Section: How Existing Therapies Affect Dcsmentioning

confidence: 99%

Dendritic cells in multiple sclerosis: key players in the immunopathogenesis, key players for new cellular immunotherapies?

et al. 2013

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Many studies have demonstrated the role of the adaptive immune system in the pathogenesis of multiple sclerosis (MS). Recent data suggest that dendritic cells (DCs), which are innate immune cells, also contribute to the pathogenesis of MS. In patients with MS, DCs are abundantly present in brain lesions, and display an altered phenotype and/or function as compared with this in healthy controls. DCs are thus in the position to pathologically influence the effector function of (auto-reactive) T and B cells. Interestingly, current first-line immunomodulating therapies for MS have been shown to restore DC phenotype and function, albeit in a non-specific manner. To date, clinical trials using agents specifically targeting DC function are ongoing. Moreover, several studies worldwide are currently investigating possible strategies to develop tolerogenic DCs. This review focuses on the phenotypic and functional alterations of conventional DCs and plasmacytoid DCs in patients with MS. Furthermore, we discuss how existing immunomodulating therapies for MS patients affect DC function and address future perspectives in the development of immunotherapies specifically targeting DCs.

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“…One reported mechanism of GA induced efficacy is through anti-inflammatory type II monocytes, however these cells are CD11c negative excluding this population [25,39]. CD11c+ dendritic cells have been implicated in GA mediated efficacy in vivo promoting Th2 development and increasing IL-10 production [94][95][96][97][98]. Therefore, it is likely that the observed increase in CD11c+GA+ cells in the spinal cord of GA treated mice or recipient EAE mice who received B lymphocytes from GA treated donors represents an anti-inflammatory dendritic cell population.…”

Section: Discussionmentioning

confidence: 99%

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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Dendritic cell, monocyte and T cell activation and response to glatiramer acetate in multiple sclerosis

Abstract: MS patients treated with GA show prominent changes in circulating antigen-presenting cells and CD4+ T cells. Expression of CD40 on DCs is significantly lower and associated with relapse risk in MS patients treated with GA.

Cited by 31 publications

References 29 publications

Glatiramer acetate treatment effects on gene expression in monocytes of multiple sclerosis patients

Glatiramer acetate treatment effects on gene expression in monocytes of multiple sclerosis patients

Dendritic cells in multiple sclerosis: key players in the immunopathogenesis, key players for new cellular immunotherapies?

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

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