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 facor 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. TSLP action is not limited to the skin - it has also been implicated in allergic responses in the lung and the nose, thus making it a common element in atopic diseases. The experiments in this proposal will test this hypothesis by 1) analyzing the role of respiratory viru-induced TSLP in driving asthma using bronchial epithelial cells from healthy and asthmatic children, as well as animal model systems;2) determine the role of TSLP in chronic airway inflammatory disease using a cockroach antigen model;3) determine whether TSLP is a factor in the atopic march, where individuals with one allergic disease are more likely to develop a second. The information gained from these studies will be critical in determining the role of TSLP in allergic lung disease, and will provide insight into whether TSLP is a therapeutic target for their treatment.

Public Health Relevance

Allergic diseases such as asthma are a growing health care problem, with greater than 10% of the population affected. In addition, it is becoming increasingly clear that early childhood respiratory virus infection increases the chances of subsequent development of airway responses to allergens. It is equally clear that respiratory virus infection can also exacerbate symptoms in patients with asthma. We propose that the cytokine thymic stromal lymphopoietin is the common element that underlies these phenomena. The experiments in this proposal will test this hypothesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI068731-08
Application #
8605497
Study Section
Special Emphasis Panel (ZRG1-IMM-G (03))
Program Officer
Minnicozzi, Michael
Project Start
2006-02-01
Project End
2017-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
8
Fiscal Year
2014
Total Cost
$423,129
Indirect Cost
$153,865
Name
Benaroya Research Institute at Virginia Mason
Department
Type
DUNS #
076647908
City
Seattle
State
WA
Country
United States
Zip Code
98101
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Larson, Ryan P; Comeau, Michael R; Ziegler, Steven F (2013) Cutting edge: allergen-specific CD4 T cells respond indirectly to thymic stromal lymphopoietin to promote allergic responses in the skin. J Immunol 190:4474-7
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Omori-Miyake, Miyuki; Ziegler, Steven F (2012) Mouse models of allergic diseases: TSLP and its functional roles. Allergol Int 61:27-34

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