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

2011; Elsevier BV; Volume: 127; Issue: 3 Linguagem: Inglês

10.1016/j.jaci.2010.12.1102

1097-6825

Mohan S. Maddur, Janakiraman Vani, Pushpa Hegde, Sébastien Lacroix‐Desmazes, Srini V. Kaveri, Jagadeesh Bayry,

Psoriasis: Treatment and Pathogenesis

BackgroundTH17 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.ObjectiveWe sought to examine whether IVIg interferes with the development and function of human TH17 cells.MethodsTH17 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.ResultsIVIg 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.ConclusionThese 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. 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. We sought to examine whether IVIg interferes with the development and function of human TH17 cells. 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. 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. 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.