The overall scope of this program is to capitalize on the availability of well-characterized T cell allergen epitopes to test specific hypotheses that arose from analysis of the data generated by the previous Large Scale Allergen Epitope Identification contracts, awarded to LIAI and Benaroya Institutes. We previously noted that in response to Timothy Grass (TG) extract, as expected TH2 cytokines predominate. However, IFN? production was associated with allergic rhinitis and IL17 with allergic asthma. Project 1 (Sette PI) will test the hypothesis that different stages (in-season versus out-of-season), types (rhinitis versus asthma) and severities of allergic disease are associated with differential magnitude of T cell responses, and also distinctive interplay of different TH subsets. Here, longitudinal studies will determine the relative size of TH subsets specific for defined epitopes both ex vivo and after in vitro expansion and we will characterize their kinetics of appearance and interplay as a function of seasonality and disease severity. Project 2 (Peters PI) will test th hypothesis that SIT treatment and clinical efficacy is associated with modulating the T cell response. Specifically, we will test the hypothesis that SIT treatment affects T cell responses to a set of novel antigens that are being identified by our laboratory that are not recognized by IgE responses. Responses to both known and novel antigens will be measured longitudinally along with multiple phenotypic T cell markers. Specific hypotheses will examine the role of Tfh subsets in modulating antibody responses and the role of IL10 producing cells in suppressing TH2 responses. Project 3 (Rao PI) will identify epigenetic signatures that correlate with asthma development and severity, as well as SIT treatment, by comparing histone modifications and DNA methylation/ hydroxymethylation patterns in epitope specific T cells isolated from blood of asthmatic versus allergic rhinitis patients. Extensive preliminary data indicates that the interpla between transcription factors and epigenetic mechanisms not only initiates immune cell differentiation but also maintains the long-term differentiated state. Accordingly, we will test th hypothesis that asthma is characterized by long-range epigenetic changes at relevant disease-associated genomic loci. The outcome of the proposed research will be the generation of validated allergen epitope data, and its dissemination to the scientific community. This will fulfil the intent of the RFA "Allergen Epitope Research and Validation Centers", provide new insight into the targets and the nature of T cell responses in allergic disease, and provide potential avenues for diagnostic and therapeutic intervention.

Public Health Relevance

Despite the high incidence of allergic disease and the prominent T cell responses associated with allergic reaction, relatively little data exists characterizing allergen-derived epitope fragments and associated T cells. This application studies the nature of these responses and their evolution during seasons, treatment and as a function of different diseases (asthma versus rhinitis). These studies may reveal cellular and molecular pathways associated with allergic disease, and thus might suggest new therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI100275-02
Application #
8442249
Study Section
Special Emphasis Panel (ZAI1-PA-I (J1))
Program Officer
Minnicozzi, Michael
Project Start
2012-04-01
Project End
2017-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
2
Fiscal Year
2013
Total Cost
$1,747,355
Indirect Cost
$629,356
Name
La Jolla Institute
Department
Type
DUNS #
603880287
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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Oseroff, Carla; Christensen, Lars H; Westernberg, Luise et al. (2016) Immunoproteomic analysis of house dust mite antigens reveals distinct classes of dominant T cell antigens according to function and serological reactivity. Clin Exp Allergy :
Seumois, Grégory; Zapardiel-Gonzalo, Jose; White, Brandie et al. (2016) Transcriptional Profiling of Th2 Cells Identifies Pathogenic Features Associated with Asthma. J Immunol 197:655-64
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Engel, Isaac; Seumois, Grégory; Chavez, Lukas et al. (2016) Innate-like functions of natural killer T cell subsets result from highly divergent gene programs. Nat Immunol 17:728-39
Oseroff, Carla; Pham, John; Frazier, April et al. (2016) Immunodominance in allergic T-cell reactivity to Japanese cedar in different geographic cohorts. Ann Allergy Asthma Immunol 117:680-689.e1
Carrasco Pro, Sebastian; Sidney, John; Paul, Sinu et al. (2015) Automatic Generation of Validated Specific Epitope Sets. J Immunol Res 2015:763461
Paul, Sinu; Lindestam Arlehamn, Cecilia S; Scriba, Thomas J et al. (2015) Development and validation of a broad scheme for prediction of HLA class II restricted T cell epitopes. J Immunol Methods 422:28-34

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