The acute phase of asthma is characterized largely by rapid cell infiltration in the lungs driven by airborne? allergens. However, chronic asthma is characterized by progressive airway remodeling, involving bronchiolar? subepithelial fibrosis and an increase in airway smooth muscle (ASM). It has been proposed that the? increase in ASM and fibrosis may be the primary factor contributing to long-term airway hypersensitivity and? as such its control is of major interest. CD4 T cells secreting Th2 cytokines might be responsible for driving? much of the pathology associated with asthma, but most information on the molecular regulation of asthma? has been obtained from murine models that only mimic the acute phase1 and do not generally result in? fibrosis or increases in ASM. Thus, in terms of chronic asthma and airway remodeling, there is presently little? information on the role, contribution, or stage of response where any cell type, including CD4 cells, might be? critical. Our overall hypothesis in this application is that CD4 T cells are important contributors to chronic? asthmatic reactions and both indirectly through effects on eosinophils and mast cells, and directly through? effects on epithelial cells and ASM, they will, regulate progressive airway remodeling over time. We have? spent much of the past few years trying to understand the membrane-expressed receptors that regulate T? cells, in particular members of the TNF/TNFR superfamily that act as costimulatory receptors. We already? have extensive, published and unpublished, data showing the critical importance of two sets of interactions,? namely OX40-OX40L and LIGHT-LTbR-HVEM to development of acute asthmatic inflammation. However,? there have currently been no studies of any costimulatory molecules and whether they participation in? chronic asthma, and specifically regulate airway remodeling. Recent studies have visualized expression of? OX40L, LTbR, and HVEM, on smooth muscle, epithelial cells, mast cells, and eosinophils, providing a strong? rationale for these ligands and their receptors, OX40 and LIGHT, expressed on T cells to control chronic? asthma. By using knockout mice and blocking reagents, and employing novel TCR transgenic systems? where we can track antigen-reactive Th2 cells that express or lack OX40 or LIGHT, in mice deficient in either? LTbR, HVEM, or OX40L, we will show if and how these novel receptor-ligand systems control airway? remodeling.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI070535-03
Application #
7684689
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2008-09-01
Budget End
2009-08-31
Support Year
3
Fiscal Year
2008
Total Cost
$376,052
Indirect Cost
Name
University of California San Diego
Department
Type
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Unno, Hirotoshi; Miller, Marina; Rosenthal, Peter et al. (2018) Activating transcription factor 6? (ATF6?) regulates airway hyperreactivity, smooth muscle proliferation, and contractility. J Allergy Clin Immunol 141:439-442.e4
Miller, Marina; Vuong, Christine; Garcia, Meghan Farrell et al. (2018) Does reduced zona pellucida binding protein 2 (ZPBP2) expression on chromosome 17q21 protect against asthma? J Allergy Clin Immunol 142:706-709.e4
Ordovas-Montanes, Jose; Dwyer, Daniel F; Nyquist, Sarah K et al. (2018) Allergic inflammatory memory in human respiratory epithelial progenitor cells. Nature 560:649-654
Herro, Rana; Shui, Jr-Wen; Zahner, Sonja et al. (2018) LIGHT-HVEM signaling in keratinocytes controls development of dermatitis. J Exp Med 215:415-422
Chen, Jun; Miller, Marina; Unno, Hirotoshi et al. (2018) Orosomucoid-like 3 (ORMDL3) upregulates airway smooth muscle proliferation, contraction, and Ca2+ oscillations in asthma. J Allergy Clin Immunol 142:207-218.e6
White, Andrew A; Doherty, Taylor A (2018) Role of group 2 innate lymphocytes in aspirin-exacerbated respiratory disease pathogenesis. Am J Rhinol Allergy 32:7-11
Mehta, Amit K; Gracias, Donald T; Croft, Michael (2018) TNF activity and T cells. Cytokine 101:14-18
Karta, Maya R; Rosenthal, Peter S; Beppu, Andrew et al. (2018) ?2 integrins rather than ?1 integrins mediate Alternaria-induced group 2 innate lymphoid cell trafficking to the lung. J Allergy Clin Immunol 141:329-338.e12
Mehta, A K; Doherty, T; Broide, D et al. (2018) Tumor necrosis factor family member LIGHT acts with IL-1? and TGF-? to promote airway remodeling during rhinovirus infection. Allergy 73:1415-1424
Doherty, Taylor A; Broide, David H (2018) Lipid regulation of group 2 innate lymphoid cell function: Moving beyond epithelial cytokines. J Allergy Clin Immunol 141:1587-1589

Showing the most recent 10 out of 106 publications