The allergic form of asthma is driven by an immune response to airborne allergens, and can be exacerbated by a number of factors including exposure to viruses. A typical signature of disease is the accumulation in the lungs of Th2 lymphocytes, eosinophils, mast cells, fibroblasts, and macrophages. Whereas the acute phase of asthma is characterized largely by rapid cell infiltration in the lungs, chronic asthma is characterized by progressive airway remodeling which includes epithelial cell mucus metaplasia, smooth muscle hypertrophy/hyperplasia, subepithelial fibrosis, and increased angiogenesis. Fibrosis is due to deposition of extracellular matrix proteins such as collagen, fibronectin, tenascin, and laminin, thought produced largely from differentiating fibroblasts or epithelial cells, which can additionally be induced to express alpha smooth muscle actin and contribute to the enhanced smooth muscle mass. How all of these cell types are controlled is largely unknown. This proposal will focus on several members of the tumor necrosis factor (TNF) and TNF receptor superfamily, and test the hypotheses that OX40 (CD134) interacting with OX40L (CD252), and LIGHT (CD258) interacting with two receptors, HVEM (CD270) and LTBR (lymphotoxin beta receptor), are signatures of allergen-induced inflammation and remodeling in lungs of patients with varying severity of asthma;that these molecules will be further induced in the lungs of patients that are exposed to rhinovirus, a pathogen that has been associated with asthma exacerbations;and that they will be functionally relevant to the inflammatory and remodeling activities of bronchial epithelial cells, and lung macrophages, fibroblasts, and T cells. The treatment options for asthmatics are currently limited. Understanding when and where these TNF/TNFR family molecules are expressed, and the functional activities that result from their interactions, might lead to new and novel targets for therapeutic intervention in both acute and chronic asthma.

Public Health Relevance

LIGHT, OX40L, and their receptors are expressed on the surface of many immune and some non-immune cells, and are thought to regulate the ability to mount certain immune responses. There is little known about the expression and activities of these proteins in human asthma and in clinical specimens from asthmatics of varying severity. By understanding where and when LIGHT and OX40L and their partners are expressed, and the functional importance of these interactions, we will gain knowledge that might lead to ways to therapeutically suppress asthma and fibrotic disease.

National Institute of Health (NIH)
Research Program--Cooperative Agreements (U19)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Diego
La Jolla
United States
Zip Code
Chang, Jinny E; Doherty, Taylor A; Baum, Rachel et al. (2014) Prostaglandin D2 regulates human type 2 innate lymphoid cell chemotaxis. J Allergy Clin Immunol 133:899-901.e3
Cho, Jae Youn; Doshi, Ashmi; Rosenthal, Peter et al. (2014) Smad3-deficient mice have reduced esophageal fibrosis and angiogenesis in a model of egg-induced eosinophilic esophagitis. J Pediatr Gastroenterol Nutr 59:10-6
Croft, Michael (2014) The TNF family in T cell differentiation and function--unanswered questions and future directions. Semin Immunol 26:183-90
Nonaka, Motohiro; Bao, Xingfeng; Matsumura, Fumiko et al. (2014) Synthetic di-sulfated iduronic acid attenuates asthmatic response by blocking T-cell recruitment to inflammatory sites. Proc Natl Acad Sci U S A 111:8173-8
Ge, Xiao Na; Ha, Sung Gil; Rao, Amrita et al. (2014) Endothelial and leukocyte heparan sulfates regulate the development of allergen-induced airway remodeling in a mouse model. Glycobiology 24:715-27
Miller, Marina; Rosenthal, Peter; Beppu, Andrew et al. (2014) ORMDL3 transgenic mice have increased airway remodeling and airway responsiveness characteristic of asthma. J Immunol 192:3475-87
Miyazaki, Masaki; Miyazaki, Kazuko; Chen, Shuwen et al. (2014) Id2 and Id3 maintain the regulatory T cell pool to suppress inflammatory disease. Nat Immunol 15:767-76
Cho, Jae Youn; Rosenthal, Peter; Miller, Marina et al. (2014) Targeting AMCase reduces esophageal eosinophilic inflammation and remodeling in a mouse model of egg induced eosinophilic esophagitis. Int Immunopharmacol 18:35-42
Suzukawa, Maho; Miller, Marina; Rosenthal, Peter et al. (2013) Sialyltransferase ST3Gal-III regulates Siglec-F ligand formation and eosinophilic lung inflammation in mice. J Immunol 190:5939-48
Croft, Michael; Benedict, Chris A; Ware, Carl F (2013) Clinical targeting of the TNF and TNFR superfamilies. Nat Rev Drug Discov 12:147-68

Showing the most recent 10 out of 57 publications