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Inhibition of differentiation, amplification, and function of human TH17 cells by intravenous immunoglobulin  Mohan S. Maddur, DVM, Janakiraman Vani,

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Presentation on theme: "Inhibition of differentiation, amplification, and function of human TH17 cells by intravenous immunoglobulin  Mohan S. Maddur, DVM, Janakiraman Vani,"— Presentation transcript:

1 Inhibition of differentiation, amplification, and function of human TH17 cells by intravenous immunoglobulin  Mohan S. Maddur, DVM, Janakiraman Vani, PhD, Pushpa Hegde, MSc, Sebastien Lacroix-Desmazes, PhD, Srini V. Kaveri, DVM, PhD, Jagadeesh Bayry, DVM, PhD  Journal of Allergy and Clinical Immunology  Volume 127, Issue 3, Pages e7 (March 2011) DOI: /j.jaci Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Fig 1 Inhibition of human TH17 cell differentiation by IVIg. A, Flow cytometric analysis of intracellular IL-17 and IFN-γ in naive TH cells after 6 days of culture for TH17 cell differentiation. A representative dot plot of 8 independent experiments is shown. B, Percentage of IL-17A+, RORC+, IL-17A+/IFN-γ+, and Foxp3+ cells (means ± SEMs, n = 8 donors) during TH17 cell differentiation. *P < .05, paired t test. Journal of Allergy and Clinical Immunology  , e7DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 Fig 2 IVIg-mediated suppression of TH17 cytokines and chemokine by the differentiating TH17 cells. The figure depicts the amount (in picograms per milliliter) of secretion of IL-17A (A), IL-17F (B), IL-21 (C), and CCL20 (D) by the naive TH cells after 6 days of culture for TH17 cell differentiation. Results (means ± SEMs) are from 8 healthy donors. *P < .05, paired t test. Journal of Allergy and Clinical Immunology  , e7DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 Fig 3 Inhibition of human TH17 cell amplification by IVIg. A, Flow cytometric analysis of intracellular IL-17 and IFN-γ in the memory TH cells after 6 days of culture for TH17 amplification. Results are representative of 8 independent experiments. B, Percentage of IL-17A+, RORC+, IL-17A+/IFN-γ+, and Foxp3+ cells (means ± SEMs, n = 8 donors) during TH17 amplification. *P < .05, paired t test. Journal of Allergy and Clinical Immunology  , e7DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 Fig 4 Suppression of TH17 cytokines and chemokine in the amplifying memory TH17 cells by IVIg. The figure shows the amount (in picograms per milliliter) of secretion of IL-17A (A), IL-17F (B), IL-21 (C), and CCL20 (D) by the memory TH cells after 6 days of culture for TH17 amplification. Results (means ± SEMs) are from 8 healthy donors. *P < .05, paired t test. Journal of Allergy and Clinical Immunology  , e7DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

6 Fig 5 IVIg-mediated suppression of differentiation and amplification of TH17 cells is F(ab′)2 dependent. The amount (in picograms per milliliter) of secretion of IL-17A, IL-17F, IL-21, and CCL20 by the naive CD4+ T cells cultured for TH17 cell differentiation (A) and the memory CD4+ T cells cultured for TH17 amplification (B) is depicted. Results (means ± SEMs) are from 5 donors. *P < .05, paired t test. Journal of Allergy and Clinical Immunology  , e7DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

7 Fig 6 IVIg modulates the sustained phosphorylation of STAT3 to mediate inhibition of TH17 cell differentiation and amplification. A, Phosphorylation status of STAT3 (pSTAT3) at indicated time points, as analyzed by means of flow cytometry. B, Mean expression of intracellular pSTAT3 levels (percentage of pSTAT3+ cells × pSTAT3 mean fluorescence intensity [MFI]) in naive TH cells (left panel) and memory TH cells (right panel). Results are representative of 3 independent experiments. Journal of Allergy and Clinical Immunology  , e7DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

8 Comparison of the inhibitory effect of IVIg and other known inhibitors on human TH17 cells. Amount of secretion of IL-17A (in picograms per milliliter, means ± SEMs, n = 3 donors) in differentiating (A) and amplifying (B) TH17 cells under the influence of IFN-β (2,000 IU/mL), 1, 25-dihydroxyvitamin D3 (Vit D3; 100 nmol/L), dexamethasone (1,000 nmol/L; Dexa), pioglitazone (PIO; 10 μmol/L), and IVIg (25 mg/mL) is shown. *P < .05, paired t test. Journal of Allergy and Clinical Immunology  , e7DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

9 Kinetic study of the effect of IVIg (25 mg/mL) on TH17 cell differentiation and amplification. Amount of secretion of IL-17A (in picograms per milliliter) during differentiation (A) and amplification (B) of TH17 cells is shown. Results are representative of one of the 3 independent experiments. Journal of Allergy and Clinical Immunology  , e7DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

10 Dose-dependent effect of IVIg on human TH17 cell differentiation and amplification. Amount of secretion of IL-17A (in picograms per milliliter, means ± SEMs, n = 5 donors) during differentiation (A) and amplification (B) of TH17 cells is shown. IVIg was added at concentrations of 5, 10, 15, 20, and 25 mg/mL. *P < .05, paired t test. Journal of Allergy and Clinical Immunology  , e7DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

11 Time-dependent effect of IVIg on human TH17 cell differentiation and amplification. Amount of secretion of IL-17A (in picograms per milliliter, means ± SEMs, n = 5 donors) during differentiation (A) and amplification (B) of TH17 cells is shown. IVIg (25 mg/mL) was added to the cells at −12, 0, 12, 24, 48, and 72 hours after cytokine stimulation. *P < .05, paired t test. Journal of Allergy and Clinical Immunology  , e7DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

12 Long-lasting inhibitory effect of IVIg on human TH17 cell differentiation and amplification. Secretion of IL-17A (in picograms per milliliter, means ± SEMs, n = 3-5 donors) during differentiation (A) and amplification (B) of TH17 cells is shown. After the first round of treatment, cells were washed and restimulated (LL) only with anti-CD3 and anti-CD28 in the presence of cytokines. LL, Long-lasting. *P < .05, paired t test. Journal of Allergy and Clinical Immunology  , e7DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

13 IVIg and F(ab′)2 fragments of IVIg bind to TH cells
IVIg and F(ab′)2 fragments of IVIg bind to TH cells. A, Flow cytometric analysis of binding of biotinylated IVIg, F(ab′)2 fragments, and HSA to CD4+ T cells. B, Percentage (means ± SEMs, n = 3) of IVIg-, F(ab′)2-, and HSA-bound TH cells. FITC, Fluorescein isothiocyanate. *P < .05, paired t test. Journal of Allergy and Clinical Immunology  , e7DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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