The long-term goals of this project are to understand the immunobiology of asthma and allergic disease. While our understanding of the role of Th2 responses in the pathogenesis of asthma as rapidly improved over the past 10 years, our knowledge of the mechanisms that dampen Th2 biased inflammatory responses and that protect against the development of Th2 inflammation and asthma remains rudimentary. Th1 cells may have a role in protection against allergy, however, our studies in murine systems indicate that multiple additional mechanisms play more critical roles in regulating asthma and allergy. We propose to identify and examine in detail these additional mechanisms that down-modulate Th2 responses in humans, and determine the cell types and molecules that participate in the protection against Th2-biased inflammation. We will identify the immunological mechanisms that prevent allergic diseases by examining allergic individuals who have successfully completed a course of allergen immunotherapy, as well as non-allergic individuals who are chronically exposed to inhaled allergen. These individuals tolerate exposure to inhaled allergen because they have developed allergen-specific protective immune responses, which we will study to gain insight into protective immunity against asthma and allergy. To assess immune responses in these non-symptomatic individuals, we will use new technologies, including gene expression profiling with cDNA microarrays and fluorescent staining with MHC class 11-peptide tetramers. By comparing gene expression profiles in cells from allergic individuals before and after allergen immunotherapy, and in cells from allergic and non-allergic individuals, we will develop a distinctive molecular portrait of the biology of, and identify specific genes and pathways important in, protective immunity. By using MHC class II-peptide tetramers; we will accurately quantitate changes in the frequency and function of allergen specific cells that occur with allergen immunotherapy. These studies, using cutting edge technologies and with collaborators who are leaders in their fields, will greatly extend our knowledge of immune responses that protect again asthma and allergy, and of Th2 biased immune responses that are pathologic for asthma and allergy. These studies therefore, are likely to lead to greatly improved therapies that protect against and potentially cure asthma and allergic diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI026322-15
Application #
6753516
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Sawyer, Richard T
Project Start
1989-07-01
Project End
2004-12-31
Budget Start
2004-06-01
Budget End
2004-12-31
Support Year
15
Fiscal Year
2004
Total Cost
$116,248
Indirect Cost
Name
Stanford University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Chuang, Ya-Ting; Leung, Krystle; Chang, Ya-Jen et al. (2018) A natural killer T-cell subset that protects against airway hyperreactivity. J Allergy Clin Immunol :
Kasahara, David I; Kim, Hye Y; Mathews, Joel A et al. (2014) Pivotal role of IL-6 in the hyperinflammatory responses to subacute ozone in adiponectin-deficient mice. Am J Physiol Lung Cell Mol Physiol 306:L508-20
Albacker, Lee A; Chaudhary, Vinod; Chang, Ya-Jen et al. (2013) Invariant natural killer T cells recognize a fungal glycosphingolipid that can induce airway hyperreactivity. Nat Med 19:1297-304
Kim, Hye Young; Chang, Ya-Jen; Subramanian, Srividya et al. (2012) Innate lymphoid cells responding to IL-33 mediate airway hyperreactivity independently of adaptive immunity. J Allergy Clin Immunol 129:216-27.e1-6
Chang, Ya-Jen; Kim, Hye Young; Albacker, Lee A et al. (2011) Innate lymphoid cells mediate influenza-induced airway hyper-reactivity independently of adaptive immunity. Nat Immunol 12:631-8
Chang, Ya-Jen; Kim, Hye Young; Albacker, Lee A et al. (2011) Influenza infection in suckling mice expands an NKT cell subset that protects against airway hyperreactivity. J Clin Invest 121:57-69
Umetsu, Dale T; Dekruyff, Rosemarie H (2010) Natural killer T cells are important in the pathogenesis of asthma: the many pathways to asthma. J Allergy Clin Immunol 125:975-9
Kim, Hye Young; DeKruyff, Rosemarie H; Umetsu, Dale T (2010) The many paths to asthma: phenotype shaped by innate and adaptive immunity. Nat Immunol 11:577-84
Lee, Hyun-Hee; Meyer, Everett H; Goya, Sho et al. (2010) Apoptotic cells activate NKT cells through T cell Ig-like mucin-like-1 resulting in airway hyperreactivity. J Immunol 185:5225-35
Tachdjian, Raffi; Al Khatib, Shadi; Schwinglshackl, Andreas et al. (2010) In vivo regulation of the allergic response by the IL-4 receptor alpha chain immunoreceptor tyrosine-based inhibitory motif. J Allergy Clin Immunol 125:1128-1136.e8

Showing the most recent 10 out of 68 publications