FoodallergyisincreasinglyprevalentintheUnitedStates,andapproximatelyone-thirdofpatientshave reactivitytomultiplefoods.Thereisanunmetclinicalneedtotreatmulti-foodallergyinatimelyandefficacious manner,butthemechanisticfactorsthatshouldguideselectionofanoptimaltreatmentstrategyareunclear. ThisprojectaimstoobtainfundamentalnewunderstandingofhumanBcellandimmunoglobulin(Ig) responsesinpatientsallergictomultiplefoods,andtoanalyzetheBcellalterationsinducedbymulti-allergen oralimmunotherapy(multi-OIT)aloneorincombinationwithbiologicstargetingIgEortheIL-4/IL-13receptor componentIL-4R?.Wewilluseflowcytometryisolationofallergen-specificBcells,focusingoncellsspecific formilk,peanutorcashewallergens,pairedwithDNAdeepsequencingofimmunoglobulin(Ig)gene rearrangements,tocharacterizepathogenicBcellpopulationsinallergicpatients,andtodeterminewhat changesinclonalpopulations,antibodyisotypeexpression,antibodysomaticmutation,andaffinityareinduced intheseBcellpopulationsduringsuccessfulmulti-OITtreatment.WewillevaluatewhetherthereareBcell repertoirefeatures,eitherpriortomulti-OIT,orduringmulti-OIT,thatpredictparticipants?responsesandcould beusedtoguidetherapy.Thestudieswillbeperformedonspecimensfromwell-characterizedmulti-allergic participantsinthepilot,phase2multi-OITclinicaltrialproposedinProject1,aswellasfromappropriate atopicandhealthycontrolsubjects.WewillevaluateandcomparethemolecularfeaturesofBcellsand antibodiesspecificformilk,peanutandcashewallergens,andtheiralterationsinresponsetomulti-OIT,within thesamepeople.Inasubsetofparticipants,wewillstudyBcellsinbothbloodandGIbiopsyspecimens,to determinetowhatextentperipheralbloodBcellmonitoringaccuratelyreflectstheallergicdiseasestateinthe GItractofpatients,andthechangesinducedbymulti-OIT.Importantly,wewillalsoanalyzetheeffectsof monoclonalantibodytherapiestargetingIgEorIL-4R?duringmulti-OIT,todeterminetheextenttowhichthese biologictherapiesaffectthenatureandtimecourseofBcellchangesinducedbymulti-OIT.Wewilladditionally performlong-termfollowupstudiesofBcellsinparticipantsinourPOISEDandMAPXOITtrials. TheBcelldatafromthisProjectwillbecombinedandanalyzedtogetherwithclinicaldataandexperimental datafromTcellsandbasophilsfromProjects1,3and4,andCoreB,incollaborationwiththeDataAnalysis CoreC,toenableacomprehensiveevaluationofimmunologicalphenotypesassociatedwithmulti-food allergicdisease,andwithsuccessfulanddurabletherapeuticresponsestomulti-OIT.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI104209-08
Application #
10092909
Study Section
Special Emphasis Panel (ZAI1)
Project Start
2013-07-01
Project End
2024-01-31
Budget Start
2021-02-01
Budget End
2022-01-31
Support Year
8
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Stanford University
Department
Type
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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Mukai, Kaori; Tsai, Mindy; Saito, Hirohisa et al. (2018) Mast cells as sources of cytokines, chemokines, and growth factors. Immunol Rev 282:121-150
Keren, Leeat; Bosse, Marc; Marquez, Diana et al. (2018) A Structured Tumor-Immune Microenvironment in Triple Negative Breast Cancer Revealed by Multiplexed Ion Beam Imaging. Cell 174:1373-1387.e19
Chinthrajah, R Sharon; Purington, Natasha; Andorf, Sandra et al. (2018) Development of a tool predicting severity of allergic reaction during peanut challenge. Ann Allergy Asthma Immunol 121:69-76.e2
Andorf, Sandra; Purington, Natasha; Block, Whitney M et al. (2018) Anti-IgE treatment with oral immunotherapy in multifood allergic participants: a double-blind, randomised, controlled trial. Lancet Gastroenterol Hepatol 3:85-94
Tsai, Cheng-Ting; Mukai, Kaori; Robinson, Peter V et al. (2018) Isotype-specific agglutination-PCR (ISAP): A sensitive and multiplex method for measuring allergen-specific IgE. J Allergy Clin Immunol 141:1901-1904.e15
Gaudenzio, Nicolas; Marichal, Thomas; Galli, Stephen J et al. (2018) Genetic and Imaging Approaches Reveal Pro-Inflammatory and Immunoregulatory Roles of Mast Cells in Contact Hypersensitivity. Front Immunol 9:1275
Purington, Natasha; Chinthrajah, R Sharon; Long, Andrew et al. (2018) Eliciting Dose and Safety Outcomes From a Large Dataset of Standardized Multiple Food Challenges. Front Immunol 9:2057
Hartmann, Felix J; Simonds, Erin F; Bendall, Sean C (2018) A Universal Live Cell Barcoding-Platform for Multiplexed Human Single Cell Analysis. Sci Rep 8:10770

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