Mechanisms of action of glatiramer acetate in multiple sclerosis

Neuhaus, Oliver; Farina, Cinthia; Wekerle, Hartmut; Hohlfeld, Reinhard

doi:10.1212/wnl.56.6.702

Cited by 240 publications

(137 citation statements)

References 83 publications

(128 reference statements)

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“…31). With respect to the binding of GA to immune cells, in vitro experiments have shown that GA binds promiscuously to class II MHC (32)(33)(34), thereby competing with MBP-derived peptides for the MBP-specific TCR (35)(36)(37).…”

Section: Discussionmentioning

confidence: 99%

Glatiramer Acetate (Copolymer-1, Copaxone) Promotes Th2 Cell Development and Increased IL-10 Production Through Modulation of Dendritic Cells

Vieira¹,

Heystek²,

Wormmeester³

et al. 2003

The Journal of Immunology

201

145

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Glatiramer acetate (GA; copolymer-1, Copaxone) suppresses the induction of experimental autoimmune encephalomyelitis and reduces the relapse frequency in relapsing-remitting multiple sclerosis. Although it has become clear that GA induces protective degenerate Th2/IL-10 responses, its precise mode of action remains elusive. Because the cytokine profile of Th cells is often regulated by dendritic cells (DC), we studied the modulatory effects of GA on the T cell regulatory function of human DC. This study shows the novel selective inhibitory effect of GA on the production of DC-derived inflammatory mediators without affecting DC maturation or DC immunostimulatory potential. DC exposed to GA have an impaired capacity to secrete the major Th1 polarizing factor IL-12p70 in response to LPS and CD40 ligand triggering. DC exposed to GA induce effector IL-4-secreting Th2 cells and enhanced levels of the anti-inflammatory cytokine IL-10. The anti-inflammatory effect of GA is mediated via DC as GA does not affect the polarization patterns of naive Th cells activated in an APC-free system. Together, these results reveal that APC are essential for the GA-mediated shift in the Th cell profiles and indicate that DC are a prime target for the immunomodulatory effects of GA.

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Section: Discussionmentioning

confidence: 99%

Glatiramer Acetate (Copolymer-1, Copaxone) Promotes Th2 Cell Development and Increased IL-10 Production Through Modulation of Dendritic Cells

Vieira¹,

Heystek²,

Wormmeester³

et al. 2003

The Journal of Immunology

201

145

View full text Add to dashboard Cite

show abstract

“…8,9 Although different potential mechanisms have been considered, most investigations have attributed the immunomodulatory activity of GA to alterations in T-cell antigen reactivity, focusing on its influence on the adaptive immune response. Early in vitro studies established that GA can bind to major histocompatibility complex (MHC) class II molecules and suggested that GA might preferentially alter presentation of myelin antigens to auto-reactive T-cells.…”

Section: Introductionmentioning

confidence: 99%

Mechanism of Action of Glatiramer Acetate in Treatment of Multiple Sclerosis

2007

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Summary:Glatiramer acetate (GA) (Copolymer-1, Copaxone, Teva, Israel, YEAK) is a polypeptide-based therapy approved for the treatment of relapsing-remitting multiple sclerosis. Most investigations have attributed the immunomodulatory effect of GAs to its capability to alter T-cell differentiation. Specifically, GA treatment is believed to promote development of Th2-polarized GA-reactive CD4 ϩ T-cells, which may dampen neighboring inflammation within the central nervous system. Recent reports indicate that the deficiency in CD4 FoxP3ϩ regulatory Tcells in multiple sclerosis is restored by GA treatment. GA also exerts immunomodulatory activity on antigen presenting cells, which participate in innate immune responses. These new findings represent a plausible explanation for GA-mediated T-cell immune modulation and may provide useful insight for the development of new and more effective treatment options for multiple sclerosis.

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“…However, the mechanisms of GA action are still elusive. Initial investigations attributed most GA activity to a preferential Th2-polarization of myelin-specific T cells, thus focusing on its effects on the adaptive immune response (3). However, recent reports indicated that GA treatment also exerts immunomodulatory activity on cells of the monocytic lineage, i.e., monocytes/macrophages and dendritic cells (4)(5)(6)(7)(8)(9).…”

mentioning

confidence: 99%

Glatiramer acetate increases IL-1 receptor antagonist but decreases T cell-induced IL-1β in human monocytes and multiple sclerosis

Burger

Molnarfi

Weber

et al. 2009

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

127

113

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Mechanisms of action as well as cellular targets of glatiramer acetate (GA) in multiple sclerosis (MS) are still not entirely understood. IL-1␤ is present in CNS-infiltrating macrophages and microglial cells and is an important mediator of inflammation in experimental autoimmune encephalitis (EAE), the MS animal model. A natural inhibitor of IL-1␤, the secreted form of IL-1 receptor antagonist (sIL-1Ra) improves EAE disease course. In this study we examined the effects of GA on the IL-1 system. In vivo, GA treatment enhanced sIL-1Ra blood levels in both EAE mice and patients with MS, whereas IL-1␤ levels remained undetectable. In vitro, GA per se induced the transcription and production of sIL-1Ra in isolated human monocytes. Furthermore, in T cell contactactivated monocytes, a mechanism relevant to chronic inflammation, GA strongly diminished the expression of IL-1␤ and enhanced that of sIL-1Ra. This contrasts with the effect of GA in monocytes activated upon acute inflammatory conditions. Indeed, in LPSactivated monocytes, IL-1␤ and sIL-1Ra production were increased in the presence of GA. These results demonstrate that, in chronic inflammatory conditions, GA enhances circulating sIL-1Ra levels and directly affects monocytes by triggering a bias toward a less inflammatory profile, increasing sIL-1Ra while diminishing IL-1␤ production. This study sheds light on a mechanism that is likely to participate in the therapeutic effects of GA in MS.experimental autoimmune encephalitis ͉ cellular contact ͉ inflammation ͉ autoimmune disease

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Mechanisms of action of glatiramer acetate in multiple sclerosis

Cited by 240 publications

References 83 publications

Glatiramer Acetate (Copolymer-1, Copaxone) Promotes Th2 Cell Development and Increased IL-10 Production Through Modulation of Dendritic Cells

Glatiramer Acetate (Copolymer-1, Copaxone) Promotes Th2 Cell Development and Increased IL-10 Production Through Modulation of Dendritic Cells

Mechanism of Action of Glatiramer Acetate in Treatment of Multiple Sclerosis

Glatiramer acetate increases IL-1 receptor antagonist but decreases T cell-induced IL-1β in human monocytes and multiple sclerosis

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