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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