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CD4 T-helper cells engineered to produce IL-10 prevent allergen-induced airway hyperreactivity and inflammation  Jae-Won Oh, MD, PhD, Christine M. Seroogy,

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Presentation on theme: "CD4 T-helper cells engineered to produce IL-10 prevent allergen-induced airway hyperreactivity and inflammation  Jae-Won Oh, MD, PhD, Christine M. Seroogy,"— Presentation transcript:

1 CD4 T-helper cells engineered to produce IL-10 prevent allergen-induced airway hyperreactivity and inflammation  Jae-Won Oh, MD, PhD, Christine M. Seroogy, MD, Everett H. Meyer, MS, Omid Akbari, PhD, Gerald Berry, MD, C.Garrison Fathman, MD, Rosemarie H. DeKruyff, MD, Dale T. Umetsu, MD, PhD  Journal of Allergy and Clinical Immunology  Volume 110, Issue 3, Pages (September 2002) DOI: /mai Copyright © 2002 Mosby, Inc. Terms and Conditions

2 Fig. 1 Cytokine profiles of cell lines used in these studies. T-cell lines were generated from DO11.10 mice, as discussed in the Materials and Methods section. OVA-specific TH2 cells, IL-10 cDNA-transduced cells, and vector-transduced control cells were stimulated with concanavalin A (1 μg/mL) for 18 hours in Dulbecco modified Eagle medium containing 10% FCS. Supernatants were collected and analyzed by ELISA for IL-4, IL-5, IL-13, IL-10, and IFN-γ. Results represent means ± SDs. Journal of Allergy and Clinical Immunology  , DOI: ( /mai ) Copyright © 2002 Mosby, Inc. Terms and Conditions

3 Fig. 2 A, IL-10-transduced cells inhibit TH2-induced AHR in SCID mice. SCID mice received OVA-specific TH2 (2.5 × 106 cells/mouse), IL-10 cDNA-transduced (2.0 × 106 cells/mouse), or vector-transduced control cells intravenously. OVA was administered intranasally 18 hours before cell transfer and again 24 and 48 hours after cell transfer; AHR was measured 96 hours after cell transfer. B, Anti-IL-10 mAb abolishes the inhibitory effect of the IL-10-transduced cells. Neutralizing mAb JES5-2A5 specific for IL-10 (500 μg/mouse) or control mAb 4G10 was given intraperitoneally to SCID mice 24 hours before adoptive cell transfer. SCID mice received either a mixture of IL-10 cDNA-transduced cells and OVA-specific TH2 cells intravenously or TH2 cells alone. OVA was administered intranasally 6 hours before cell transfer and again 24 and 48 hours after cell transfer, and AHR was measured 96 hours after cell transfer. Results are provided as mean percentages (± SEMs) above baseline of Penh. Journal of Allergy and Clinical Immunology  , DOI: ( /mai ) Copyright © 2002 Mosby, Inc. Terms and Conditions

4 Fig. 3 Dose-dependent inhibition of TH2-induced AHR by IL-10-transduced cells. SCID mice received OVA-specific TH2 (2.5 × 106 cells/mouse) with or without IL-10 cDNA-transduced cells (0.25 to 2.0 × 106 cells/mouse). Results are expressed as mean percentages (± SEMs) above baseline of Penh. Each group represents the mean results from 4 to 9 mice. Journal of Allergy and Clinical Immunology  , DOI: ( /mai ) Copyright © 2002 Mosby, Inc. Terms and Conditions

5 Fig. 4 OVA-specific IL-10-transduced cells inhibit the development of AHR in immunocompetent BALB/c mice in an antigen-specific manner. Immunocompetent BALB/c mice were sensitized and challenged with KLH or OVA in a standard fashion to induce AHR. In this protocol, mice were sensitized with antigen in alum on day 0. Seven days later, some mice received IL-10 cDNA-transduced cells or vector-transduced control cells intravenously (2.5 × 106 cells/mouse on day 7). All of the mice were challenged intranasally on days 7, 8, and 9 with OVA or KLH (50 μg in 50 μL of PBS). AHR was measured 24 hours after the last intranasal dose of OVA (on day 10). Data are expressed as mean percentages (± SEMs) above baseline of Penh. Journal of Allergy and Clinical Immunology  , DOI: ( /mai ) Copyright © 2002 Mosby, Inc. Terms and Conditions

6 Fig. 5 Treatment with anti-IL-10 mAb exacerbates AHR and increases IL-4 production in mice sensitized and challenged with OVA. A, BALB/c mice were sensitized with OVA in alum intraperitoneally on day 9 and challenged with OVA (50 μg intranasally × 3) on days 7, 8, and 9. Some mice received anti-IL-10 mAb (n = 9) or isotype control (n = 10) (500 μg intraperitoneally) 4 days after sensitization and again 1 day before intranasal challenge. Data are expressed as mean percentages (± SEMs) above baseline of Penh and are representative of 3 experiments. B, Treatment with anti-IL-10 mAb increases IL-4 production. Bronchial lymph node T cells from mice sensitized and challenged with OVA were cultured at 5 × 105 cells/well with 50 μg/mL OVA. IL-4 in culture supernatants was determined after 4 days of culture. Data represent means of triplicate cytokine determinations ± SDs (5 mice/group). Representative results from one of 2 experiments are presented. Journal of Allergy and Clinical Immunology  , DOI: ( /mai ) Copyright © 2002 Mosby, Inc. Terms and Conditions

7 Fig. 6 Airway inflammation is increased in mice treated with anti-IL-10 mAb. A, Airway inflammation is present in lung tissue from a mouse sensitized intraperitoneally and challenged with intranasal OVA. Lung tissue was removed on day 11. A peribronchiolar mixed inflammatory infiltrate of lymphocytes and eosinophils is present in the peribronchiolar space (hematoxylin-eosin; ×250). Insert: High-power magnification of bronchiolar lining cells shows abundant intracytoplasmic mucin and eosinophils in the peribronchiolar space (hematoxylin-eosin; ×400). B, Nonsensitized (naive) mouse show normal airway histology (hematoxylin-eosin; ×250). Insert: Bronchioles are lined by low cuboidal epithelium (hematoxylin-eosin; ×600). C, Marked airway inflammation is seen in lung tissue of a mouse sensitized and challenged with OVA and treated with anti-IL-10 mAb on day 4 and day 6. The airway lumen is filled and expanded with mucus secretions, and an intense peribronchiolar infiltrate is present (hematoxylin-eosin; ×250). Insert: High-power magnification of the airway epithelium shows abundant luminal and intracytoplasmic mucin in tall columnar epithelial lining cells as well as eosinophils in the peribronchiolar space (hematoxylin-eosin; ×400). D, Lung tissue from a nonsensitized (naive) mouse receiving anti-IL-10 mAb shows normal airway histology (hematoxylin-eosin; ×250). Insert: High-power magnification shows bronchiolar lining cells composed of low cuboidal cells that are devoid of inflammation and intracytoplasmic mucin (hematoxylin-eosin; ×600). Journal of Allergy and Clinical Immunology  , DOI: ( /mai ) Copyright © 2002 Mosby, Inc. Terms and Conditions

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