Asthma is a disease characterized by reversible airflow obstruction and bronchial inflammation. The goal of this proposal is to understand how environmental antigens influence local immunologic processes in the lung and airways and result in the inflammatory infiltrate and bronchial hyperresponsiveness seen in this disease. There is considerable recent evidence that CD4+ T lymphocytes (Th2 cells) that secrete interleukin-4 and interleukin-5 are involved in the pathogenesis of asthma. These cytokines are associated with airway eosinophilia and high IgE levels that are typically seen in atopic asthmatics. We plan to study airway inflammation and bronchial hyperresponsiveness in the mouse by investigating the role of inhaled antigens in the induction of pulmonary Th2 cells. The induction of Th2 cells during an immune response has been shown to be influenced by three factors: the antigen itself, the type of antigen presenting cell that interacts with the T cell, and the cytokines present at the site of CD4 T cell stimulation. We will use three groups of transgenic mice which will allow us to investigate how each of these factors individually effects Th2 cell induction in the lung and airways. Once we have established conditions that control Th2 dominant responses in the lung, we will examine pulmonary histopathology and measure airway resistance in provoked mice. Thus, we will test our hypothesis that airway hyperresponsiveness and inflammation are associated with selective pulmonary Th2 lymphocyte activation. Further, we will investigate methods to abrogate Th2 responses once they are established. From these studies we hope to gain insight into how the immunologic responses associated with asthma can be manipulated. Overall, we hope to shed light on the complex immunopathogenesis of airway inflammation and its association with bronchial hyperresponsiveness in a transgenic mouse model.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Lung Biology and Pathology Study Section (LBPA)
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Yale University
Schools of Medicine
New Haven
United States
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Albrecht, Melanie; Arnhold, Markus; Lingner, Sandra et al. (2012) IL-4 attenuates pulmonary epithelial cell-mediated suppression of T cell priming. PLoS One 7:e45916
Albrecht, Melanie; Chen, Hui-Chen; Preston-Hurlburt, Paula et al. (2011) T(H)17 cells mediate pulmonary collateral priming. J Allergy Clin Immunol 128:168-177.e8
Dokmeci, Elif; Xu, Lan; Robinson, Eve et al. (2011) EBI3 deficiency leads to diminished T helper type 1 and increased T helper type 2 mediated airway inflammation. Immunology 132:559-66
Tan, Anna M; Chen, Hui-Chen; Pochard, Pierre et al. (2010) TLR4 signaling in stromal cells is critical for the initiation of allergic Th2 responses to inhaled antigen. J Immunol 184:3535-44
Dittrich, Anna M; Chen, Hui-Chen; Xu, Lan et al. (2008) A new mechanism for inhalational priming: IL-4 bypasses innate immune signals. J Immunol 181:7307-15
Cook, Donald N; Bottomly, Kim (2007) Innate immune control of pulmonary dendritic cell trafficking. Proc Am Thorac Soc 4:234-9
Piggott, Damani A; Eisenbarth, Stephanie C; Xu, Lan et al. (2005) MyD88-dependent induction of allergic Th2 responses to intranasal antigen. J Clin Invest 115:459-67
Eisenbarth, Stephanie C; Zhadkevich, Alex; Ranney, Patricia et al. (2004) IL-4-dependent Th2 collateral priming to inhaled antigens independent of Toll-like receptor 4 and myeloid differentiation factor 88. J Immunol 172:4527-34
Eisenbarth, Stephanie C; Piggott, Damani A; Huleatt, James W et al. (2002) Lipopolysaccharide-enhanced, toll-like receptor 4-dependent T helper cell type 2 responses to inhaled antigen. J Exp Med 196:1645-51
Cohn, L; Herrick, C; Niu, N et al. (2001) IL-4 promotes airway eosinophilia by suppressing IFN-gamma production: defining a novel role for IFN-gamma in the regulation of allergic airway inflammation. J Immunol 166:2760-7

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