Glatiramer acetate and IFN-β act on dendritic cells in multiple sclerosis

Hussien, Yassir; Sanna, Alessandra; Söderström, M.; Link, Hans; Huang, Yu‐Min

doi:10.1016/s0165-5728(01)00432-5

Cited by 86 publications

(62 citation statements)

References 40 publications

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“…IFN-b-modulated pDCs with enhanced CD123 expression and IL-10 production were previously described as a subset of myeloid DCs (29)(30)(31). Interestingly, these cells resemble the pDC1 subset described in this study and suggest that both pDC1 and pDC2 are a subset of plasmacytoid DCs and not, as hypothesized earlier (22), a possible subtype of myeloid DCs.…”

Section: Discussionsupporting

confidence: 76%

An Imbalance of Two Functionally and Phenotypically Different Subsets of Plasmacytoid Dendritic Cells Characterizes the Dysfunctional Immune Regulation in Multiple Sclerosis

Schwab¹,

Zozulya²,

Kieseier

et al. 2010

The Journal of Immunology

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Section: Discussionsupporting

confidence: 76%

An Imbalance of Two Functionally and Phenotypically Different Subsets of Plasmacytoid Dendritic Cells Characterizes the Dysfunctional Immune Regulation in Multiple Sclerosis

Schwab¹,

Zozulya²,

Kieseier

et al. 2010

The Journal of Immunology

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“…Hitherto, there is no information regarding the effects of GA on the effector function of DC. Very recently, Hussien et al (49) reported that the presence of GA during the in vitro generation of immature DC from human peripheral blood monocytes inhibited the capacity of these immature DC to produce biologically inactive IL-12p40. This study left the question whether GA could directly modulate the production of bioactive IL-12p70 of immature DC or could modulate the maturation of these DC and consequently their capacity to induce Th1 responses unanswered.…”

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

204

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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“…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). For instance, monocytes from GAtreated patients with MS secrete less IL-12 and TNF in response to LPS stimulation compared with monocytes from healthy controls and untreated patients with MS (4).…”

mentioning

confidence: 99%

“…For instance, monocytes from GAtreated patients with MS secrete less IL-12 and TNF in response to LPS stimulation compared with monocytes from healthy controls and untreated patients with MS (4). Accordingly, dendritic cells and monocytes isolated from GA-treated patients produce more anti-inflammatory IL-10 and less pro-inflammatory IL-12 (5,9). Furthermore, GA promotes the development of anti-inflammatory type II monocytes in EAE, accompanied by induction of regulatory T cells and increased secretion of both IL-10 and TGF-␤ (10).…”

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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Glatiramer acetate and IFN-β act on dendritic cells in multiple sclerosis

Cited by 86 publications

References 40 publications

An Imbalance of Two Functionally and Phenotypically Different Subsets of Plasmacytoid Dendritic Cells Characterizes the Dysfunctional Immune Regulation in Multiple Sclerosis

An Imbalance of Two Functionally and Phenotypically Different Subsets of Plasmacytoid Dendritic Cells Characterizes the Dysfunctional Immune Regulation in Multiple Sclerosis

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

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

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