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Publication Detail
Selective ERK activation differentiates mouse and human tolerogenic dendritic cells, expands antigen-specific regulatory T cells, and suppresses experimental inflammatory arthritis.
  • Publication Type:
    Journal article
  • Publication Sub Type:
    Journal Article
  • Authors:
    Arce F, Breckpot K, Stephenson H, Karwacz K, Ehrenstein MR, Collins M, Escors D
  • Publication date:
    01/2011
  • Pagination:
    84, 95
  • Journal:
    Arthritis Rheum
  • Volume:
    63
  • Issue:
    1
  • Status:
    Published
  • Country:
    United States
  • Language:
    eng
  • Keywords:
    Analysis of Variance, Animals, Arthritis, Experimental, Butadienes, Cell Differentiation, Cell Line, Cells, Cultured, Dendritic Cells, Enzyme Inhibitors, Enzyme-Linked Immunosorbent Assay, Extracellular Signal-Regulated MAP Kinases, Flavonoids, Flow Cytometry, Humans, Immune Tolerance, Inflammation, Mice, Nitriles, T-Lymphocytes, Regulatory
Abstract
OBJECTIVE: Most therapeutic treatments for autoimmune arthritis rely on immunosuppressive drugs, which have side effects. Although a previous study by our group showed that specific ERK activation suppressed immune responses, its application in a therapeutic setting has never been tested. The aim of the present study was to define the ERK-dependent immunosuppressive mechanisms and to apply selective ERK activation for the treatment of experimental inflammatory arthritis. METHODS: A constitutively active ERK activator was coexpressed with a model antigen using lentivectors. Immunosuppressive mechanisms were characterized at the level of dendritic cell (DC) function, differentiation of antigen-specific Treg cells, and inhibition of inflammatory T cells. Administration of the ERK activator with antigen as a strategy to suppress inflammatory arthritis was tested in an experimental mouse model. RESULTS: Selective ERK activation induced mouse and human DCs to secrete bioactive transforming growth factor β, a process required for suppression of T cell responses and differentiation of antigen-specific Treg cells. Treg cells strongly proliferated after antigen reencounter in inflammatory conditions, and these cells exhibited antigen-dependent suppressive activities. Inflammatory arthritis was effectively inhibited through antigen-specific mechanisms. Importantly, this strategy did not rely on identification of the initiating arthritogenic antigen. Equivalent mechanisms were demonstrated in human monocyte-derived DCs, setting the scene for a possible rapid translation of this approach to patients with rheumatoid arthritis. CONCLUSION: This strategy of selective ERK activation resulted in an effective therapeutic protocol, with substantial advantages over DC or T cell vaccination.
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