Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adjuvants, Immunologic / pharmacology*
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Antigen Presentation / drug effects
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Antigen-Presenting Cells / cytology
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Antigen-Presenting Cells / drug effects
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Antigen-Presenting Cells / immunology
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Antigen-Presenting Cells / metabolism
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Cell Differentiation / drug effects
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Cell Differentiation / immunology
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Cytokines / antagonists & inhibitors
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Cytokines / biosynthesis
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Dendritic Cells / cytology
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Dendritic Cells / drug effects*
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Dendritic Cells / immunology
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Dendritic Cells / metabolism
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Glatiramer Acetate
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Humans
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Immunosuppressive Agents / pharmacology
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Inflammation Mediators / metabolism
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Interleukin-10 / biosynthesis*
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Interleukin-12 / antagonists & inhibitors
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Interleukin-12 / biosynthesis
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Interleukin-12 / physiology
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Interleukin-4 / biosynthesis
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Interleukin-8 / antagonists & inhibitors
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Interleukin-8 / biosynthesis
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Peptides / pharmacology*
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Protein Subunits / antagonists & inhibitors
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Protein Subunits / biosynthesis
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Stem Cells / immunology
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Stem Cells / metabolism
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Th2 Cells / cytology*
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Th2 Cells / drug effects*
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Th2 Cells / immunology
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
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Tumor Necrosis Factor-alpha / biosynthesis
Substances
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Adjuvants, Immunologic
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Cytokines
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Immunosuppressive Agents
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Inflammation Mediators
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Interleukin-8
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Peptides
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Protein Subunits
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Tumor Necrosis Factor-alpha
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Interleukin-10
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Interleukin-12
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Interleukin-4
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Glatiramer Acetate