Journal
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Volume 127, Issue 3, Pages 823-U514Publisher
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2010.12.1102
Keywords
Intravenous immunoglobulin; allergy; autoimmunity; inflammation; T(H)17 cells; IL-17; regulatory T cells; retinoic-acid-related orphan receptor C; forkhead box protein 3
Categories
Funding
- Institut National de la Sante et de la Recherche Medicale (INSERM)
- Centre National de la Recherche Scientifique (CNRS)
- Universite Pierre et Marie Curie
- Universite Paris Descartes
- European Community [HEALTH-F2-2010-260338-ALLFUN]
- Octapharma
- Lachen, Switzerland
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Background: T(H)17 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 T(H)17 cells to exert therapeutic effects. Objective: We sought to examine whether IVIg interferes with the development and function of human T(H)17 cells. Methods: T(H)17 cells were differentiated from naive human CD4(+) T cells in the presence of TGF-beta and IL-21. T(H)17 cells were amplified by stimulating memory CD4(+) T cells in the presence of IL-1 beta and IL-6. The effect of IVIg was examined on the differentiation and amplification of T(H)17 cells, expression of the T(H)17 lineage-specific transcription factor retinoic acid-related orphan receptor C, secretion of T(H)17 effector cytokines, and phosphorylation of signal transducer and activator of transcription 3, a transcription factor that plays an important role in T(H)17 cell development and function. Results: IVIg inhibits the differentiation and amplification of human T(H)17 cells, as well as the production of their effector cytokines IL-17A, IL-17F, IL-21, and CCL20. The inhibitory effects of IVIg on T(H)17 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 T(H)17 cells play a key modulatory role in sustaining the chronic inflammatory response. Our results also suggest a reciprocal regulation of T(H)17 and regulatory T-cell populations by IVIg. (J Allergy Clin Immunol 2011;127:823-30.)
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