Most cases of asthma are allergic in origin and are characterized by eosinophilic airway inflammation associated with mucous hypersecretion and airways hyper-responsiveness (AHR). Airway inflammation in asthma results from an allergic-type reaction to an inhaled antigen (allergen) from the environment. It is now clear that this reaction is primarily orchestrated by CD4[+] MHC class II restricted T cells that recognize and become activated by specific allergens via their T cell receptor. The asthma phenotype is thought to be primarily driven by Th2-type CD4[+] T cells;however, other CD4[+] T cell subsets, such as Th1 cells, Th17 cells and regulatory T cells (Tregs) have also been implicated in asthma pathogenesis. In this proposal, we will use MHC class II tetramers to specifically identify and study allergen-specific T cells recovered from the airways and blood following endobronchial segmental allergen challenge (SAC) in human subjects. We will compare the numbers, phenotype and function of effector and regularoty T cells recovered from two groups of allergic subjects: allergic asthmatics (AA) and allergic non-asthmatics (ANA). For unclear reasons, ANA subjects have symptomatic allergic inflammation to common aeroallergens in the skin, nose and/or eyes, but do not have symptoms of asthma. We hypothesize that there are fundamental differences in the T cell response in the lung to allergens in AA when compared to ANA subjects that account for the difference in the clinical response. In this project we will correlate the phenotypic and functioanl differences in T cell subtypes in these subjects to changes in airway physiology following SAC utilizing novel and innovative PET-CT imaging techniques.
The specific aims are: 1) To determine the correlation between airway inflammation and AHR following SAC;2) To determine the phenotype of allergen-specific and bulk CD4[+] T cells in the blood and airway following SAC;3) To identify the mechanisms that control T cell activation and activity in the airways following SAC;4) To determine the numbers, phenotype and function of Tregs in the airway following SAC. This proposal will define the phenotype of T cells in asthma, the mechanisms that control their activity, and the links between allergic airway inflammation and AHR.

Public Health Relevance

Asthma remains an important source of morbidity and health care costs in the U.S. Allergen-specific T cells are thought to be the primary inducers of airway inflammation that leads to the symptoms of asthma while regulatory T cells inhibit these responses and symptoms. This project will characterize in detail the T cell populations that mediate or suppress allergic airway inflammation and airways hyper-responsiveness.

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
Massachusetts General Hospital
United States
Zip Code
Riol-Blanco, Lorena; Ordovas-Montanes, Jose; Perro, Mario et al. (2014) Nociceptive sensory neurons drive interleukin-23-mediated psoriasiform skin inflammation. Nature 510:157-61
Millet, Yves A; Alvarez, David; Ringgaard, Simon et al. (2014) Insights into Vibrio cholerae intestinal colonization from monitoring fluorescently labeled bacteria. PLoS Pathog 10:e1004405
Griffith, Jason W; Luster, Andrew D (2013) Targeting cells in motion: migrating toward improved therapies. Eur J Immunol 43:1430-5
Sperandio, Markus; Quackenbush, Elizabeth J; Sushkova, Natalia et al. (2013) Ontogenetic regulation of leukocyte recruitment in mouse yolk sac vessels. Blood 121:e118-28
Islam, Sabina A; Ling, Morris F; Leung, John et al. (2013) Identification of human CCR8 as a CCL18 receptor. J Exp Med 210:1889-98
Wang, Chen; Yi, Tai; Qin, Lingfeng et al. (2013) Rapamycin-treated human endothelial cells preferentially activate allogeneic regulatory T cells. J Clin Invest 123:1677-93
Hariri, Lida P; Applegate, Matthew B; Mino-Kenudson, Mari et al. (2013) Volumetric optical frequency domain imaging of pulmonary pathology with precise correlation to histopathology. Chest 143:64-74
Giallourakis, Cosmas C; Benita, Yair; Molinie, Benoit et al. (2013) Genome-wide analysis of immune system genes by expressed sequence Tag profiling. J Immunol 190:5578-87
Afshar, Roshi; Strassner, James P; Seung, Edward et al. (2013) Compartmentalized chemokine-dependent regulatory T-cell inhibition of allergic pulmonary inflammation. J Allergy Clin Immunol 131:1644-52
Harris, R Scott; Venegas, Jose G; Wongviriyawong, Chanikarn et al. (2011) 18F-FDG uptake rate is a biomarker of eosinophilic inflammation and airway response in asthma. J Nucl Med 52:1713-20