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Inhibition of differentiation, amplification, and function of human TH17 cells by intravenous immunoglobulin

  • Mohan S. Maddur
    Affiliations
    Unité 872, Institut National de la Santé et de la Recherche Médicale Paris, Paris, France

    Centre de Recherche des Cordeliers, Equipe 16- Immunopathology and therapeutic immunointervention, Université Pierre et Marie Curie, Paris, France

    Université Paris Descartes, Paris, France
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  • Janakiraman Vani
    Affiliations
    Unité 872, Institut National de la Santé et de la Recherche Médicale Paris, Paris, France

    Centre de Recherche des Cordeliers, Equipe 16- Immunopathology and therapeutic immunointervention, Université Pierre et Marie Curie, Paris, France

    Université Paris Descartes, Paris, France
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  • Pushpa Hegde
    Affiliations
    Unité 872, Institut National de la Santé et de la Recherche Médicale Paris, Paris, France

    Universite de Technologie de Compiegne, Compiegne, France
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  • Sebastien Lacroix-Desmazes
    Affiliations
    Unité 872, Institut National de la Santé et de la Recherche Médicale Paris, Paris, France

    Centre de Recherche des Cordeliers, Equipe 16- Immunopathology and therapeutic immunointervention, Université Pierre et Marie Curie, Paris, France

    Université Paris Descartes, Paris, France

    International Associated Laboratory IMPACT, Institut National de la Santé et de la Recherche Médicale, France-Indian Council of Medical Research, Mumbai, India
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  • Srini V. Kaveri
    Correspondence
    Reprint requests: Jagadeesh Bayry, DVM, PhD, or Srini V. Kaveri, DVM, PhD, INSERM U 872, Equipe 16-Centre de Recherche des Cordeliers, 15 rue de l’Ecole de Médicine, Paris, F-75006, France.
    Affiliations
    Unité 872, Institut National de la Santé et de la Recherche Médicale Paris, Paris, France

    Centre de Recherche des Cordeliers, Equipe 16- Immunopathology and therapeutic immunointervention, Université Pierre et Marie Curie, Paris, France

    Université Paris Descartes, Paris, France

    International Associated Laboratory IMPACT, Institut National de la Santé et de la Recherche Médicale, France-Indian Council of Medical Research, Mumbai, India
    Search for articles by this author
  • Jagadeesh Bayry
    Correspondence
    Reprint requests: Jagadeesh Bayry, DVM, PhD, or Srini V. Kaveri, DVM, PhD, INSERM U 872, Equipe 16-Centre de Recherche des Cordeliers, 15 rue de l’Ecole de Médicine, Paris, F-75006, France.
    Affiliations
    Unité 872, Institut National de la Santé et de la Recherche Médicale Paris, Paris, France

    Centre de Recherche des Cordeliers, Equipe 16- Immunopathology and therapeutic immunointervention, Université Pierre et Marie Curie, Paris, France

    Université Paris Descartes, Paris, France

    International Associated Laboratory IMPACT, Institut National de la Santé et de la Recherche Médicale, France-Indian Council of Medical Research, Mumbai, India
    Search for articles by this author
Published:January 31, 2011DOI:https://doi.org/10.1016/j.jaci.2010.12.1102

      Background

      TH17 cells play a critical role in the pathogenesis of several autoimmune and allergic diseases. Intravenous immunoglobulin (IVIg), a therapeutic preparation of polyclonal IgG that is increasingly used in the treatment of diverse autoimmune and allergic diseases, might target TH17 cells to exert therapeutic effects.

      Objective

      We sought to examine whether IVIg interferes with the development and function of human TH17 cells.

      Methods

      TH17 cells were differentiated from naive human CD4+ T cells in the presence of TGF-β and IL-21. TH17 cells were amplified by stimulating memory CD4+ T cells in the presence of IL-1β and IL-6. The effect of IVIg was examined on the differentiation and amplification of TH17 cells, expression of the TH17 lineage-specific transcription factor retinoic acid-related orphan receptor C, secretion of TH17 effector cytokines, and phosphorylation of signal transducer and activator of transcription 3, a transcription factor that plays an important role in TH17 cell development and function.

      Results

      IVIg inhibits the differentiation and amplification of human TH17 cells, as well as the production of their effector cytokines IL-17A, IL-17F, IL-21, and CCL20. The inhibitory effects of IVIg on TH17 cells are F(ab′)2 dependent and involve interference with the expression of retinoic acid-related orphan receptor C and activation of signal transducer and activator of transcription 3. Also, IVIg significantly enhanced forkhead box protein 3–positive regulatory T cells among the memory CD4+ T cells.

      Conclusion

      These results reveal a novel mechanism of action of IVIg in achieving a therapeutic effect in autoimmune and allergic diseases, in which TH17 cells play a key modulatory role in sustaining the chronic inflammatory response. Our results also suggest a reciprocal regulation of TH17 and regulatory T-cell populations by IVIg.

      Key words

      Abbreviations used:

      APC (Antigen-presenting cell), Foxp3 (Forkhead box protein 3), HSA (Human serum albumin), IVIg (Intravenous immunoglobulin), pSTAT3 (Phosphorylated STAT3), RORC (Retinoic-acid-related orphan receptor C), STAT3 (Signal transducer and activator of transcription 3), Treg (Regulatory T)
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