The proposed Allergen Epitope Research and Validation Center will use unique Major Histocompatibility (MHO) class II tetramers containing T cell epitopes of the major cat allergen Pel d 1 in order to characterize allergen-specific T cells before and after intervention with (1) a peptide-based therapeutic vaccine comprised of immunodominant T cell epitopes of Pel d 1, and (2) bronchial (segmental) allergen challenge with cat allergen extract. Two research Projects and two Cores are proposed. The Cores (Administrative Core A and Clinical Trial Core B) will facilitate and support the scientific objectives and goals of the research Projects. Project 1 (peptide immunotherapy) Specific Aim 1 will use tetramers to both enrich and identify allergenspecific T cells in frozen peripheral blood mononuclear cell (PBMC) samples (before vs. after treatment) from a completed clinical trial of the peptide vaccine. Project 1 Specific Aim 2 will employ a prospective clinical trial of peptide immunotherapy to generate larger blood samples for more in depth analysis of the frequency and functional phenotype of allergen-specific (tetramer+) T cells. Project 1 Specific Aim 3 will address the relationship between peptide affinity for MHC molecules and efficacy.
This Aim will be performed in HLA-DR transgenic mice as the research question posed cannot be answered in human subjects. Project 2 (bronchial allergen challenge) Specific Aims 1 & 2 will involve segmental allergen challenge in 48 catallergic asthmatic subjects. Samples of blood and bone marrow will be taken before and 24 hours after allergen challenge. Samples of bronchoalveolar lavage (BAL) fluid will be recovered from saline and allergen challenged lung lobes 24 hours after challenge. In all samples. Pel d 1 tetramers will be used to enrich (were appropriate) and identify allergen-specific T cells for further analysis of frequency and functional phenotype in each anatomical compartment. Project 2 Specific Aim 3 will perform a similar analysis but in HLA-DR4 transgenic mice, but will analyze several other compartments not accessible in human subjects (spleen, lung tissue, draining lymph nodes in addition to blood, BAL and bone marrow). Additionally this Aim will assess the effects of peptide immunotherapy in the murine allergen challenge model
Allergic diseases represent a major public health issue. Improved understanding of the immunological mechanisms underlying the cause & development of disease, and therapeutic interventions will inform the development and refinement of novel forms of therapy.This proposal uses new epitope-specific tools to determine the frequency and function of T cells reactive with the cat allergen, Feld 1. These T cells have been shown in our previous studies to play a key role in allergic asthma and the response to immunotherapy.
|Moldaver, Daniel M; Larché, Mark; Rudulier, Christopher D (2017) An Update on Lymphocyte Subtypes in Asthma and Airway Disease. Chest 151:1122-1130|