Asthma is a major public health issue and allergy to cats is a major risk factor for the development of asthma. Studying how allergens entering the lung trigger the immune system and result in an asthma exacerbation is important as an improved understanding of the pathogenesis of asthma will inform development of new therapies. Controlled allergen challenge of the lung in the clinical laboratory is an excellent model in which to study how the immune system responds to allergen and contributes to disease
Allergen inhalation by atopic asthmatics in the laboratory results in most of the manifestations of asthma, including reversible airflow obstruction, AHR and airway inflammation. This methodology has been used to examine the mechanisms of eosinophil, T-cell, and dendritic cell trafficking to/from the bone marrow to/from the blood and to the airways. The current proposal will capitalize on the unique opportunity offered by this allergen-specific model of direct bronchial challenge, by using MHC class II allergen tetramer reagents to enrich and characterize, ex vivo, Fel d 1 epitope-specific T cells before and after a localized bronchial allergen challenge. The over arching hypothesis of this proposal is that trafficking of allergen-specific T cells (tetramer+) from the blood to the airways and bone marrow is associated with the development of the late asthmatic reaction. This study will measure the frequency of Fel d 1-specific T cells, how these cells traffic between relevant compartments (blood, bone marrow and airways) and how their functional phenotype changes in response to allergen challenge.
Specific Aim 1: To determine the frequency and functional phenotype of Fel d 1-specific (Fel d 1 MHC class II tetramer+) T cells in the blood and the airways following lung segmental allergen challenge.
Specific Aim 2: To determine the frequency and functional phenotype of Fel d 1-specific (Fel d 1 MHC class II tetramer+) T cells in the bone marrow following lung segmental allergen challenge.
Specific Aim 3: To determine the frequency and functional phenotype of Fel d 1-specific (Fel d 1 MHC class II tetramer+) T cells in the blood, the airways (BAL and digested lung tissue), the lymph nodes draining the airways, the spleen and the bone marrow following inhaled allergen challenge in an HLA-DR4-transgenic murine model of allergic airways disease, and to assess the effects of peptide immunotherapy, using components of a human vaccine currently in clinical trials, on these parameters. The results of these studies will help to clarify how allergen-specific T cells contribution to the pathogenesis of asthma and inform development of rational approaches to therapeutic intervention.