The atopic diseases consist of the triad of asthma, allergic rhinitis, and atopic dermatitis. These diseases share a common pathogenesis, involving inflammatory Th2-type cytokines and elevated IgE. Interestingly, they frequently present together in the same individual and family, suggesting common factors and mechanisms are involved in these diseases. Recent evidence has been accumulated to suggest that Th2-type CD4+ T cells play a triggering role in the activation and/or recruitment of IgE antibody-producing B cells, mast cells and eosinophils, i.e. the cellular triad involved in the allergic inflammation. However, the mechanisms underlying the preferential activation by environmental allergens of Th2 cells in atopic individuals still remain obscure. A likely candidate for such an initiating factor is the cytokine thymic stromal lymphopoietin (TSLP). TSLP is upregulated in the lungs of mice with airway inflammatory disease and humans with asthma. In addition, mice lacking TSLP responses fail to develop allergen-induced airway inflammation. Finally, TSLP is also induced in airway epithelial cells infected by respiratory viruses, suggesting a role for TSLP in these responses. Respiratory Syncytial virus (RSV) is the most important cause of lower respiratory tract infections in infants and young children. The majority of children infected with RSV experience mild respiratory symptoms with rhinorrhea, cough, and wheezing. However, 1-2% of previously healthy full term infants require hospitalization for RSV bronchiolitis. Several studies have shown that these children are at increased risk for subsequent wheezing or asthma for up to a decade following RSV bronchiolitis. Mechanisms explaining the association between RSV infection and subsequent asthma are poorly understood. The studies in this proposal are designed to test the hypothesis that TSLP, induced in airway epithelial cells following RSV infection, is critical for the subsequent development of asthma. We propose to: 1) assess the role of TSLP in the response to respiratory syncytial virus infection;2) determine whether TSLP is involved in the RSV-induced exacerbation of allergen-responses in the lung;and 3) Determine whether TSLP expression induced by RSV infection is greater in differentiated bronchial epithelial cells from asthmatic children than from atopic or healthy children without asthma. The information gained from these studies will be critical in determining the role of TSLP in the development of childhood asthma, and will provide important preclinical data for subsequent studies on the potential therapeutic efficacy of TSLP blockade for asthma.

Public Health Relevance

Allergic diseases such as asthma are a growing health care problem, with greater than 10% of the population affected. Importantly, asthma is the most common chronic lung disease in children, affecting at least 6.5 million children and causing 7 million physician visits and 200,000 hospitalizations among children annually in the U.S. In addition, it is becoming increasingly clear that early childhood respiratory virus infection increases the chances of subsequent development of airway responses to allergens. While this association between early, severe RSV infection and subsequent development of asthma is becoming clear, the underlying mechanism remains obscure. We propose that the cytokine thymic stromal lymphopoietin (TSLP) is the common element that underlies these phenomena. TSLP has been linked to allergic inflammation, including asthma, in humans. In addition, we have shown that infection of human airway cells induces the production of TSLP, suggesting a role for this cytokine in subsequent asthma development. The experiments in this proposal will test the hypothesis that production of TSLP, induced by RSV infection, is a critical component of the subsequent development of asthmatic disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HL102708-02
Application #
8236953
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Noel, Patricia
Project Start
2011-03-08
Project End
2013-08-28
Budget Start
2012-03-01
Budget End
2013-08-28
Support Year
2
Fiscal Year
2012
Total Cost
$203,917
Indirect Cost
$50,478
Name
Benaroya Research Institute at Virginia Mason
Department
Type
DUNS #
076647908
City
Seattle
State
WA
Country
United States
Zip Code
98101
Ziegler, Steven F; Roan, Florence; Bell, Bryan D et al. (2013) The biology of thymic stromal lymphopoietin (TSLP). Adv Pharmacol 66:129-55
Roan, Florence; Bell, Bryan D; Stoklasek, Thomas A et al. (2012) The multiple facets of thymic stromal lymphopoietin (TSLP) during allergic inflammation and beyond. J Leukoc Biol 91:877-86