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CD4+CD25+ regulatory T cells reverse established allergic airway inflammation and prevent airway remodeling  Jennifer Kearley, PhD, Douglas S. Robinson,

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Presentation on theme: "CD4+CD25+ regulatory T cells reverse established allergic airway inflammation and prevent airway remodeling  Jennifer Kearley, PhD, Douglas S. Robinson,"— Presentation transcript:

1 CD4+CD25+ regulatory T cells reverse established allergic airway inflammation and prevent airway remodeling  Jennifer Kearley, PhD, Douglas S. Robinson, MD, Clare M. Lloyd, PhD  Journal of Allergy and Clinical Immunology  Volume 122, Issue 3, Pages e6 (September 2008) DOI: /j.jaci Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Fig 1 Therapeutic administration of CD4+CD25+ regulatory T cells reverses allergen-induced eosinophilic airway inflammation and the lung TH2 response. Lung eosinophils (A), lung inflammation (B; hematoxylin and eosin–stained sections), TH2 (CD4+T1/ST2+) cells (C), IL-5 and IL-13 levels (D), and IL-10 (E) and TGF-β1 levels (F) in lung tissue were measured at day 33 (therapeutic inflammation protocol). Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 Fig 2 Therapeutic administration of CD4+CD25+ regulatory T cells prevents the development of airway remodeling after prolonged allergen challenge. Lung eosinophils (A), mucus production (B), total lung collagen (C), and peribronchial collagen deposition (D) were assessed at day 53 after chronic challenge (airway remodeling protocol). E, Representative lung sections stained with hematoxylin and eosin (H&E), periodic acid–Schiff (PAS), and Sirius red for each treatment group are shown. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 Fig 3 Therapeutic transfer of CD4+CD25+ regulatory T cells has no effect on established AHR. Cells were administered on day 26, and mice were killed on either day 33 (A; therapeutic inflammation protocol) or day 53 (B; airway remodeling protocol). AHR was measured and expressed as mean lung resistance (RL), as summarized for the 10 mg/mL methacholine dose. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 Fig 4 Transfer of CD4+CD25+ regulatory T cells during established remodeling (day 46) has no effect on allergen-induced airway inflammation or remodeling. Lung eosinophils (A), mucus production (B), and peribronchial collagen deposition (C) were quantified at day 53 after transfer of regulatory T cells by using the established remodeling protocol (n = 4-6 mice per group). Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

6 Fig 5 Transferred CD4+CD25+ regulatory T cells might not be recruited to the lung at later time points because of decreasing levels of proinflammatory chemokines. Transferred CD4+CD25+ regulatory T cells (A) were detected in lung tissue digest by expression of CD4 and the DO11.10 T-cell receptor. CCL22/MDC (B), CCL17/TARC (C), and CCL1/TCA-3 (D) levels were measured in lung tissue. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

7 Induction of chronic allergen-induced airway inflammation and remodeling. Airway inflammation and remodeling were induced in female BALB/c mice. Therapeutic inflammation protocol (A): Therapeutic transfer of CD4+CD25+ regulatory T cells or PBS as a control took place on day 26 after the acute challenge phase, and mice were killed for analysis on day 33. Airway remodeling protocol (B): Cells were transferred at day 26 and mice were killed for analysis at day 53 to assess the effect of transfer of CD4+CD25+ regulatory T cells on the development of airway remodeling. Established remodeling protocol (C): Mice received either CD4+CD25+ regulatory T cells or PBS on day 46 and were killed for analysis on day 53 to determine the effect of CD4+CD25+ regulatory T cells on established airway remodeling. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

8 Time course of inflammatory and airway remodeling changes during prolonged allergen challenge. Mice were assessed at days 26, 33, 46, and 53 to determine the degree of airway inflammation and remodeling throughout this prolonged allergen challenge model. BAL eosinophil numbers (A) were assessed by means of differential counting. BAL fluid TH2 cytokine levels (B) were assessed by means of ELISA. Lung mucus production (C) was assessed in periodic acid–Schiff–stained lung sections. Total lung collagen (D) was quantified by using a biochemical assay. Data are expressed as means ± SEMs (n = 6-25 mice per group). Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

9 Transfer of CD4+CD25+ regulatory T cells reduces BAL fluid eosinophilia and TH2 cytokine expression. Airways underwent lavage, and eosinophil numbers (A) were determined by means of differential counting. IL-5 and IL-13 (B), IL-10 (C), and TGF-β1 (D) levels were measured in BAL supernatant by means of ELISA. End points were measured on day 33 after the therapeutic inflammation protocol. Data are expressed as medians (Fig E3, A) or means ± SEMs (Fig E3, B-D). Results from 8 to 12 mice per group from 2 separate experiments are shown. ∗P < .05 in comparison with OVA-sensitized mice that received PBS instead of CD4+CD25+ regulatory T cells. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

10 Transfer of CD4+CD25+ regulatory T cells has no effect on serum IgE levels. Levels of total IgE (A) and OVA-specific IgE (B) were measured in sera by means of ELISA on day 33 after the therapeutic inflammation protocol. Data are expressed as means ± SEMs (n = 8-12 mice per group from 2 separate experiments. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

11 Therapeutic transfer of CD4+CD25+ regulatory T cells has no effect on established AHR. Cells were administered on day 26, and mice were killed on either day 33 (A; therapeutic inflammation protocol) or day 53 (B; airway remodeling protocol). AHR was measured and expressed as mean lung compliance (Cdyn) summarized for the 10 mg/mL methacholine dose. Data are expressed as means ± SEMs (n = mice per group from 2 separate experiments). Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

12 Transfer of CD4+CD25+ regulatory T cells during established remodeling (day 46) has no effect on allergen-induced airway inflammation or remodeling. AHR was measured and expressed as mean lung resistance (A) and compliance (B) summarized for the 10 mg/mL methacholine dose, and total lung collagen (C) values were quantified at day 53 after transfer of regulatory T cells by using the established remodeling protocol. Data are expressed as means ± SEMs (n = 4-6 mice per group). Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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