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 #
1U19AI100275-01
Application #
8325207
Study Section
Special Emphasis Panel (ZAI1-PA-I (J1))
Project Start
Project End
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
1
Fiscal Year
2012
Total Cost
$270,003
Indirect Cost
$95,208
Name
La Jolla Institute
Department
Type
DUNS #
603880287
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Schulten, Véronique; Tripple, Victoria; Seumois, Grégory et al. (2018) Allergen-specific immunotherapy modulates the balance of circulating Tfh and Tfr cells. J Allergy Clin Immunol 141:775-777.e6
Moore, Eugene; Grifoni, Alba; Weiskopf, Daniela et al. (2018) Sequence-based HLA-A, B, C, DP, DQ, and DR typing of 496 adults from San Diego, California, USA. Hum Immunol 79:821-822
Schulten, Véronique; Sette, Alessandro (2018) The Identification of Allergen-Derived T Cell Epitopes. Methods Mol Biol 1799:153-163
Schulten, Véronique; Westernberg, Luise; Birrueta, Giovanni et al. (2018) Allergen and Epitope Targets of Mouse-Specific T Cell Responses in Allergy and Asthma. Front Immunol 9:235
Glesner, Jill; Filep, Stephanie; Vailes, Lisa D et al. (2018) Allergen content in German cockroach extracts and sensitization profiles to a new expanded set of cockroach allergens determine in vitro extract potency for IgE reactivity. J Allergy Clin Immunol :
da Silva Antunes, Ricardo; Pham, John; McMurtrey, Curtis et al. (2018) Urinary Peptides As a Novel Source of T Cell Allergen Epitopes. Front Immunol 9:886
Dhanda, Sandeep Kumar; Karosiene, Edita; Edwards, Lindy et al. (2018) Predicting HLA CD4 Immunogenicity in Human Populations. Front Immunol 9:1369
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
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

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