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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
1U19AI095261-01
Application #
8196484
Study Section
Special Emphasis Panel (ZAI1-PA-I (M1))
Project Start
2011-08-05
Project End
2016-07-31
Budget Start
2011-08-05
Budget End
2012-07-31
Support Year
1
Fiscal Year
2011
Total Cost
$355,138
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Vandersarren, Lana; Bosteels, Cedric; Vanheerswynghels, Manon et al. (2017) Epitope mapping and kinetics of CD4 T cell immunity to pneumonia virus of mice in the C57BL/6 strain. Sci Rep 7:3472
Adams, David C; Hariri, Lida P; Miller, Alyssa J et al. (2016) Birefringence microscopy platform for assessing airway smooth muscle structure and function in vivo. Sci Transl Med 8:359ra131
Urso, Katia; Alvarez, David; Cremasco, Viviana et al. (2016) IL4RA on lymphatic endothelial cells promotes T cell egress during sclerodermatous graft versus host disease. JCI Insight 1:
Hondowicz, Brian D; An, Dowon; Schenkel, Jason M et al. (2016) Interleukin-2-Dependent Allergen-Specific Tissue-Resident Memory Cells Drive Asthma. Immunity 44:155-166
Young, J S; Chen, J; Miller, M L et al. (2016) Delayed Cytotoxic T Lymphocyte-Associated Protein 4-Immunoglobulin Treatment Reverses Ongoing Alloantibody Responses and Rescues Allografts From Acute Rejection. Am J Transplant 16:2312-23
Ling, Morris F; Luster, Andrew D (2016) Allergen-Specific CD4(+) T Cells in Human Asthma. Ann Am Thorac Soc 13 Suppl 1:S25-30
Proekt, Irina; Miller, Corey N; Jeanne, Marion et al. (2016) LYN- and AIRE-mediated tolerance checkpoint defects synergize to trigger organ-specific autoimmunity. J Clin Invest 126:3758-3771
Jhunjhunwala, Siddharth; Alvarez, David; Aresta-DaSilva, Stephanie et al. (2016) Frontline Science: Splenic progenitors aid in maintaining high neutrophil numbers at sites of sterile chronic inflammation. J Leukoc Biol 100:253-60
Ordovas-Montanes, Jose; Rakoff-Nahoum, Seth; Huang, Siyi et al. (2015) The Regulation of Immunological Processes by Peripheral Neurons in Homeostasis and Disease. Trends Immunol 36:578-604
Patil, Sarita U; Ogunniyi, Adebola O; Calatroni, Agustin et al. (2015) Peanut oral immunotherapy transiently expands circulating Ara h 2-specific B cells with a homologous repertoire in unrelated subjects. J Allergy Clin Immunol 136:125-134.e12

Showing the most recent 10 out of 45 publications