Two of the RFA main goals are the characterization of epitopes derived from the Large Scale Allergen Epitope Identification Contracts, 1) as a function of seasonality and 2) disease progression. Accordingly, we propose to test the hypothesis that different stages (in-season versus out-of-season), types (rhinitis versus asthma) and severities of allergic disease are associated with not only differential magnitude of T cell responses, but also distinctive patterns in terms of the TH subsets involved and their interplay. We will focus on immunodominant regions from three important allergens, namely timothy grass (TG), house dust mite (HDM) and cat dander (CD). In our first Aim, we propose to characterize responses in moderate/severe (MO/SA) and mild asthmatics (MA), and contrast them with those observed in non-asthmatic individuals suffering from allergic rhinitis (AR). Preliminary data suggest that differential ILIO, ILI7 and IFNy production correlate with different disease states. Here, we propose to characterize the subsets of TH cells producing these lymphokines ex vivo and following in vitro stimulation, by ELISPOT, intracellular cytokine staining (ICS) and tetramer staining assays. We will further examine whether the different subsets are distinct or can originate from each other in vitro, because of TH cell plasticity. Preliminary data also suggest that the relative balance of TH subsets differs substantially when TG and HDM responses are compared. We will therefore investigate whether different distributions of TH subsets correlate with allergen source. Our preliminary data further highlights dramatic differences in magnitude of TG responses as a function of seasonal exposure. In the second Aim we propose to determine in longitudinal studies response magnitude and TH functional subsets. In a further series of experiments we will perform challenge studies utilizing TG pollen extracts. We expect that because of a more vigorous response TH cells might be more easily detectable ex vivo, and characterized in greater detail without potential alterations introduced by in vitro culture. These studies will characterize the functional T cell subsets involved in different disease settings and as a function of seasonality.

Public Health Relevance

The proposed studies ask whether there are differences, either in strength or quality, in the immune responses detected in different type of allergies (AR versus asthma) or in- versus out-of-season, using well defined protein fragments (epitopes) derived from allergens such as TG pollen, HDM and CD. Understandingthe differences in response might suggest effective and safe ways to intervene to cure or prevent allergies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI100275-03
Application #
8637924
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
La Jolla Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Oseroff, Carla; Christensen, Lars H; Westernberg, Luise et al. (2017) Immunoproteomic analysis of house dust mite antigens reveals distinct classes of dominant T cell antigens according to function and serological reactivity. Clin Exp Allergy 47:577-592
Sette, Alessandro; Schulten, Véronique (2017) It's a lot of work to be nonallergic. J Allergy Clin Immunol 139:769-770
Schulten, Véronique; Tripple, Victoria; Seumois, Grégory et al. (2017) Allergen-specific immunotherapy modulates the balance of circulating Tfh and Tfr cells. J Allergy Clin Immunol :
Westernberg, Luise; Schulten, Véronique; Greenbaum, Jason A et al. (2016) T-cell epitope conservation across allergen species is a major determinant of immunogenicity. J Allergy Clin Immunol 138:571-578.e7
Schmiedel, Benjamin Joachim; Seumois, Grégory; Samaniego-Castruita, Daniela et al. (2016) 17q21 asthma-risk variants switch CTCF binding and regulate IL-2 production by T cells. Nat Commun 7:13426
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
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
Pham, J; Oseroff, C; Hinz, D et al. (2016) Sequence conservation predicts T cell reactivity against ragweed allergens. Clin Exp Allergy 46:1194-205
Schulten, V; Tripple, V; Aasbjerg, K et al. (2016) Distinct modulation of allergic T cell responses by subcutaneous vs. sublingual allergen-specific immunotherapy. Clin Exp Allergy 46:439-48
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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