The broad, long term objective of this research proposal is to understand how peptide immunotherapy, using validated T cell epitopes of a major allergen (Fel d 1), modulates the frequency and functional phenotype of Fel d 1-specific T cells, using unique MHC Class II tetramer reagents. We hypothesize that peptide immunotherapy results in modulation of the frequency and functional phenotype of allergen-specific T cells following peptide immunotherapy.
Specific Aim 1 will determine the effects of peptide immunotherapy (PIT) on Fel d 1-specific (tetramer+) T cells in subjects with cat allergic asthma of increasing severity. An archive of frozen peripheral blood mononuclear cells (PBMC) collected from a Phase II clinical trial of peptide immunotherapy in subjects with cat allergic asthma (groups stratified for severity) will be used to determine the frequency and functional phenotype of allergen-specific (MHC class II tetramer+) T cells.
Specific Aim 2 will employ a prospective clinical trial of peptide immunotherapy in cat allergic rhinitis. Large volumes (200ml) of blood will be drawn at baseline, shortly after the end of treatment (week 18-22) and one year after the initiation of the study. Tetramer+ T cells will be enriched using sequential magnetic purification to determine whether peptide immunotherapy changes frequency, memory phenotype, chemokine receptor expression and markers of regulatory T cell function among allergen-specific tetramer+ T cells.
Specific Aim 3 will address how the affinity of vaccine peptides for the MHC affects the clinical efficacy of the peptide (its ability to induce immunological tolerance). This study cannot be performed in human subject due to the complexity of MHC molecules expressed and because each peptide binds to multiple MHC molecules. Therefore the study will be conducted in mice that express the human MHC gene, HLA-DR4. The 7 peptides comprising the peptide vaccine employed in Aims 1 &2 have differing affinity for HLA-DR4. Each peptide will be evaluated to determine how efficacy relates to affinity.
Allergic diseases represent a major public health issue. Allergy to cats is strongly associated with the development of asthma. Peptide immunotherapy is a disease-modifying experimental therapy that is associated with clinical benefit that substantially exceeds the treatment period. Understanding the mechanisms by which the vaccine modulates the frequency and function of allergen-specific T cells will inform future vaccine development and identifv novel avenues for therapy.
| Moldaver, Daniel M; Larché, Mark; Rudulier, Christopher D (2017) An Update on Lymphocyte Subtypes in Asthma and Airway Disease. Chest 151:1122-1130 |
