During infancy and early childhood a subset of children with permissive genotypes develop aeroallergen hypersensitivities and asthma, while others do not. Epidemiological and laboratory investigations suggest that early life exposures to toll like receptor (TLR) ligands may have a profound impact on the genesis of asthma. Therefore, we propose to determine how airway exposures to purified TLR ligands and TLR ligands within house dust extracts (HDEs) impact on innate and adaptive immunity and subsequent responses to airway allergen challenge, in adult and 2-week old mice SA-I: Characterize how early life airway exposures to peptidoglycan (PGN; TLR2), LPS (TLR4) and immunostimulatory sequence oIigodeoxynucleotide (ISS-ODN; TLR9) influence innate and adaptive immunity and airway allergen tolerance- TLR2, TLR4, and TLR9 ligands are known to be ubiquitous and to induce divergent immunological responses. Therefore, we will compare PGN, LPS, and ISS-ODN induced maturation of lung associated DCs and their subsequent functionality in the immunological synapse with naive CD4 cells. In vitro and in vivo models will be utilized in comparative analyses of adult and 2-week old mice. In additional experiments, mice will be i.n. immunized with OVA alone or with PGN, LPS, or ISS-ODN, and immune and airway allergen challenge responses will be analyzed. SA-2: Characterize how early life airway exposures to TLR ligands contained in house dust extracts (HDEs) influence innate and adaptive immunity and airway allergen tolerance- Studies with purified PGN, LPS, and ISS-ODN will help define their unique immunological activities in the lungs. However, in the real world, potential asthmatic infants and toddlers are likely to have simultaneous exposures to a variety of TLR ligands and potentially other immunostimulatory elements, as well. Therefore, to complement studies with purified TLR ligands, we will first measure the LPS and Gram positive and negative bacterial DNA content of t-HDEs from homes that are tolerance (homes with livestock, dogs and cats etc.) and homes permissive for Th2 biased airway allergen hypersensitivities (homes without animal exposures). Then in studies analogous to those proposed in SA-1, we will determine how HDEs from tolerogenic and asthma permissive homes influence airway DC maturation, CD4 cell differentiation, and host susceptibility towards aeroallergen hypersensitivities in adult and 2 week old mice.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI061772-04
Application #
7174856
Study Section
Special Emphasis Panel (ZAI1-KLW-I (M6))
Program Officer
Togias, Alkis
Project Start
2004-08-05
Project End
2009-01-31
Budget Start
2007-02-01
Budget End
2008-01-31
Support Year
4
Fiscal Year
2007
Total Cost
$292,988
Indirect Cost
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Kim, Haejin; Tse, Kevin; Levin, Linda et al. (2012) House dust bioactivities predict skin prick test reactivity for children with high risk of allergy. J Allergy Clin Immunol 129:1529-37.e2
Wingender, Gerhard; Rogers, Paul; Batzer, Glenda et al. (2011) Invariant NKT cells are required for airway inflammation induced by environmental antigens. J Exp Med 208:1151-62
Horner, Anthony A (2010) Regulation of aeroallergen immunity by the innate immune system: laboratory evidence for a new paradigm. J Innate Immun 2:107-13
Horner, A A; Kawakami, T (2009) Allergen-independent immunomodulatory activities of immunoglobulin E. Clin Exp Allergy 39:304-6
Tse, Kevin; Horner, Anthony A (2008) Allergen tolerance versus the allergic march: the hygiene hypothesis revisited. Curr Allergy Asthma Rep 8:475-83
Lam, Diane; Ng, Nicholas; Lee, Steve et al. (2008) Airway house dust extract exposures modify allergen-induced airway hypersensitivity responses by TLR4-dependent and independent pathways. J Immunol 181:2925-32
Tse, Kevin; Horner, Anthony A (2008) Defining a role for ambient TLR ligand exposures in the genesis and prevention of allergic diseases. Semin Immunopathol 30:53-62
Batzer, Glenda; Lam, Diane P; Paulus, Petra et al. (2007) Using house dust extracts to understand the immunostimulatory activities of living environments. Immunobiology 212:491-8
Tse, Kevin; Horner, Anthony A (2007) Update on toll-like receptor-directed therapies for human disease. Ann Rheum Dis 66 Suppl 3:iii77-80
Ng, Nicholas; Lam, Diane; Paulus, Petra et al. (2006) House dust extracts have both TH2 adjuvant and tolerogenic activities. J Allergy Clin Immunol 117:1074-81

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