Peanut allergy (PA) Is an increasingly common form of food allergy associated with severe clinical reactions to peanut, Including fatal anaphylaxis. Recent studies in children (less than 18 years) have provided evidence that oral immunotherapy (OIT) can reduce the sensitivity of PA patients to peanut. However, it is not yet clear to what extent such patients have developed desensitization/non-tolerance, defined as a lack of clinical reactivity to peanut that requires ongoing exposure to peanut for this muted clinical reactivity to peanut to be maintained, as oppose to tolerance, in which the patient exhibits a long term and perhaps permanent loss of reactivity to peanut^""""""""^. In the Phase 2 clinical trial of peanut OIT that will be conducted in Project 1 of this U19 proposal, we will determine which subjects develop desensitization/non-tolerance vs. tolerance to peanut. In this project, we will investigate changes in the T cell populations of PA subjects who respond to OIT, in order to identify changes that might contribute to the development of tolerance. We particularly will focus on changes in regulatory T cells (Treg) in PA patients who exhibit favorable responses to OIT. After characterizing and quantifying the modulation of T cell phenotype and function associated with peanut OIT, we will then test the results of these experiments for possible correlation with the development of tolerance vs. non-tolerance in PA patients who respond favorably to peanut OIT. Our main hypothesis is that memory T effector cells (Teff) specific to peanut allergen are converted Into Treg through epigenetic changes in the FOXPS locus that increase FOXPS expression, resulting In improved Treg function, as reflected In a Treg-dependent reduction of Teff proliferation in response to peanut. To test this hypothesis, we propose to:
(Aim 1) Characterize the immunophenotypic and functional changes induced by OIT in specific T cell populations in patients with PA;
(Aim 2) Quantify epigenetic changes (I.e., methylation of CpG islands) in key loci (i.e., F0XP3) to assess whether such changes are associated with enhancement of Treg function and favorable clinical outcomes in OIT;
and (Aim 3) Use MHC class II multimer-based methods to characterize the specificity of T cell recognition of peanut peptides. If we achieve these aims, we expect our results to provide new insights into the mechanisms underlying tolerance to food allergens, and to Improve understanding ofthe immune changes that contribute to the durability and safety of oral Immunotherapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI104209-02
Application #
8605847
Study Section
Special Emphasis Panel (ZAI1-PA-I)
Project Start
Project End
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
2
Fiscal Year
2014
Total Cost
$272,507
Indirect Cost
$98,936
Name
Stanford University
Department
Type
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Andorf, Sandra; Borres, Magnus P; Block, Whitney et al. (2017) Association of Clinical Reactivity with Sensitization to Allergen Components in Multifood-Allergic Children. J Allergy Clin Immunol Pract 5:1325-1334.e4
Balbino, Bianca; Sibilano, Riccardo; Starkl, Philipp et al. (2017) Pathways of immediate hypothermia and leukocyte infiltration in an adjuvant-free mouse model of anaphylaxis. J Allergy Clin Immunol 139:584-596.e10
Galli, Stephen J; Starkl, Philipp; Marichal, Thomas et al. (2017) Mast Cells and IgE can Enhance Survival During Innate and Acquired Host Responses to Venoms. Trans Am Clin Climatol Assoc 128:193-221
Mukai, Kaori; Gaudenzio, Nicolas; Gupta, Sheena et al. (2017) Assessing basophil activation by using flow cytometry and mass cytometry in blood stored 24 hours before analysis. J Allergy Clin Immunol 139:889-899.e11
Boyd, Scott Dexter; Hoh, Ramona Amy; Nadeau, Kari Christine et al. (2017) Immune monitoring for precision medicine in allergy and asthma. Curr Opin Immunol 48:82-91
Andorf, Sandra; Manohar, Monali; Dominguez, Tina et al. (2017) Observational long-term follow-up study of rapid food oral immunotherapy with omalizumab. Allergy Asthma Clin Immunol 13:51
MacGinnitie, Andrew J; Rachid, Rima; Gragg, Hana et al. (2017) Omalizumab facilitates rapid oral desensitization for peanut allergy. J Allergy Clin Immunol 139:873-881.e8
Reber, Laurent L; Sibilano, Riccardo; Starkl, Philipp et al. (2017) Imaging protective mast cells in living mice during severe contact hypersensitivity. JCI Insight 2:
Reber, Laurent L; Gillis, Caitlin M; Starkl, Philipp et al. (2017) Neutrophil myeloperoxidase diminishes the toxic effects and mortality induced by lipopolysaccharide. J Exp Med 214:1249-1258
Sampath, Vanitha; Tupa, Dana; Graham, Michelle Toft et al. (2017) Deciphering the black box of food allergy mechanisms. Ann Allergy Asthma Immunol 118:21-27

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