SIT is widely accepted as a useful treatment of allergic disease despite an incomplete knowledge of mechanism of action and variability in efficacy. This project is focused on understanding mechanisms behind SIT and specifically tests the hypothesis that certain allergens, antigens, and epitopes are more prominently or potentially differentially recognized by SIT treated donors as compared to untreated allergic individuals. We further test the related hypothesis that responses to certain novel anfigens, recently identified by our group, may play a role in the successful outcome of SIT treatment. By characterizing the functional phenotype ofthe T cell responses to the known and novel antigens alike, we will identify changes occurring as a result of SIT. We will also test two specific hypotheses on mechanisms associated with SIT, namely: 1) SIT modulates Tfh cells to promote a shift from IgE to IgG production and that 2) SIT induces Tri cells with suppressive regulatory capacity. Previous work from our group in the Timothy grass (TG) system delineated the major epitopes associated with ten known major allergens in allergic and SIT treated donors. In those major TG allergens, we did not identify major targets of ILIO producing T cells. Recent data from our group using a transcriptome and proteome analysis of TG pollen and 2D gel immunoblots with IgE and IgG antibodies from SIT and allergic donors has led to the identification of several novel antigens that are selectively recognized by antibodies from SIT individuals, induce IgG (but not IgE) responses, and others that do not induce an antibody response. Several of these novel antigens are vigorously recognized by T cells, particularly from PBMC from SIT donors. Our studies will test the hypothesis that qualitative shifts in response specificity may be important in inducing efficacy of SIT. Epitopes from both known and novel antigens will be used in longitudinal studies, monitoring magnitude and phenotype of responding T cells. If successful, the proposed studies will highlight potentially useful novel immunogens for use in place of current SIT that may be safer and more effective. In addition, our studies may identify biomarkers that indicate successful SIT treatment.

Public Health Relevance

The mechanisms of allergy specific immunotherapy (SIT, also referred to as 'allergy shots') works are not fully understood. The use of crude allergen extracts has limitations in terms of safety and efficacy. We propose to study the effects of SIT on the type of T cell immune response of individuals allergic to Timothy grass. Our studies could identify the immunological basis and mode of action of SIT, and thereby suggest more effective and safer 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 #
5U19AI100275-02
Application #
8442252
Study Section
Special Emphasis Panel (ZAI1-PA-I)
Project Start
Project End
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
2
Fiscal Year
2013
Total Cost
$245,333
Indirect Cost
$82,645
Name
La Jolla Institute
Department
Type
DUNS #
603880287
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Pham, J; Oseroff, C; Hinz, D et al. (2016) Sequence conservation predicts T cell reactivity against ragweed allergens. Clin Exp Allergy 46:1194-205
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
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
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
Hinz, D; Seumois, G; Gholami, A M et al. (2016) Lack of allergy to timothy grass pollen is not a passive phenomenon but associated with the allergen-specific modulation of immune reactivity. Clin Exp Allergy 46:705-19
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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