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The Effect of Cd4+ T Cell Derived Heparin-Binding Epidermal Growth Factor in a Model of Acute Allergic Asthma
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A1295 - The Effect of Cd4+ T Cell Derived Heparin-Binding Epidermal Growth Factor in a Model of Acute Allergic Asthma
Author Block: S. Farahnak, L. Simon, M. Chen, J. G. Martin; McGill University, Montreal, QC, Canada.
Rationale: Allergic asthma is a T helper 2 (Th2) driven inflammatory disease characterized by eosinophilic inflammation, Th2-associated cytokine production, airway hyperresponsiveness (AHR), and airway remodeling. Heparin-binding epidermal growth factor (HB-EGF), associated with severe asthma and airway remodeling, can be expressed by CD4+ T cells. In this study, the aim was to investigate the pathophysiological role of CD4+ T cell derived HB-EGF in asthma in a mouse model. Methods: HB-EGF mRNA and protein expression was assessed by qPCR and ELISA, respectively, after stimulating splenocytes from ovalbumin (OVA) specific TCR transgenic mice (DO.11.10) with OVA in vitro for 72 hours and purifying CD4+ T cells by magnetic activated cell sorting. HB-EGF expression in differentiated CD4+ T cells was quantified by flow cytometry after sensitizing and challenging BALB/c mice with OVA. To examine the pathophysiological role of CD4+ T cell derived HB-EGF, tamoxifen inducible HB-EGFlox/lox/CD4-Cre+ mice were challenged intranasally after sensitization to OVA and treatment with tamoxifen (5mg/animal) for five consecutive days. AHR was evaluated with the constant-phase model in response to inhaled aerosolized methacholine. Inflammatory cell populations were quantified in bronchoalveolar lavage (BAL) and cytokine expression by CD4+ T cells was evaluated by flow cytometry. Results: CD4+ T cells increase HB-EGF expression at both protein and mRNA levels upon activation with cognate ligand in vitro. HB-EGF expression was detectable in IFN-γ, IL-4, IL-17 and Foxp3-expressing CD4+ T cells in vivo. Mice with HB-EGF knockdown in CD4+ cells exhibit less eosinophilia, lower AHR in peripheral airways, and smaller populations of IFN- γ, IL-5, and IL-13 expressing CD4+ T cells in the lung. Furthermore, there was a reduction in IL-5 expression by pulmonary CD4+ T cells. Conclusion: HB-EGF expressed by CD4+ T cells exacerbates AHR and eosinophilia, possibly by inducing IL-5 expression in CD4+ T cells. These results suggest that HB-EGF derived from CD4+ T cells plays a role in the airway pathophysiology found during allergic asthma.
Author Block: S. Farahnak, L. Simon, M. Chen, J. G. Martin; McGill University, Montreal, QC, Canada.
Rationale: Allergic asthma is a T helper 2 (Th2) driven inflammatory disease characterized by eosinophilic inflammation, Th2-associated cytokine production, airway hyperresponsiveness (AHR), and airway remodeling. Heparin-binding epidermal growth factor (HB-EGF), associated with severe asthma and airway remodeling, can be expressed by CD4+ T cells. In this study, the aim was to investigate the pathophysiological role of CD4+ T cell derived HB-EGF in asthma in a mouse model. Methods: HB-EGF mRNA and protein expression was assessed by qPCR and ELISA, respectively, after stimulating splenocytes from ovalbumin (OVA) specific TCR transgenic mice (DO.11.10) with OVA in vitro for 72 hours and purifying CD4+ T cells by magnetic activated cell sorting. HB-EGF expression in differentiated CD4+ T cells was quantified by flow cytometry after sensitizing and challenging BALB/c mice with OVA. To examine the pathophysiological role of CD4+ T cell derived HB-EGF, tamoxifen inducible HB-EGFlox/lox/CD4-Cre+ mice were challenged intranasally after sensitization to OVA and treatment with tamoxifen (5mg/animal) for five consecutive days. AHR was evaluated with the constant-phase model in response to inhaled aerosolized methacholine. Inflammatory cell populations were quantified in bronchoalveolar lavage (BAL) and cytokine expression by CD4+ T cells was evaluated by flow cytometry. Results: CD4+ T cells increase HB-EGF expression at both protein and mRNA levels upon activation with cognate ligand in vitro. HB-EGF expression was detectable in IFN-γ, IL-4, IL-17 and Foxp3-expressing CD4+ T cells in vivo. Mice with HB-EGF knockdown in CD4+ cells exhibit less eosinophilia, lower AHR in peripheral airways, and smaller populations of IFN- γ, IL-5, and IL-13 expressing CD4+ T cells in the lung. Furthermore, there was a reduction in IL-5 expression by pulmonary CD4+ T cells. Conclusion: HB-EGF expressed by CD4+ T cells exacerbates AHR and eosinophilia, possibly by inducing IL-5 expression in CD4+ T cells. These results suggest that HB-EGF derived from CD4+ T cells plays a role in the airway pathophysiology found during allergic asthma.
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