Foodallergy(FA)affects8%ofchildrenand5%ofadultsintheU.S.,and30%ofthosehaveclinical reactivitytomultiplefoods.In2independentphase1clinicaltrials,weshowedthatsimultaneousoral desensitization(D)tomultiplefoodallergens(multi-OIT)issafeandfeasible,andcanbeachievedin6-9 monthswithanti-IgEadjunctivetherapy.PolarizationofnaveTcellsintoIL-4-secretingTh2cellsisthefirst stepleadingtoallergicresponses.Thus,understandinghowmodulationofTcellresponsescanleadtoD orsustainedunresponsiveness(SU)duringsuccessfulOITiscritical.WeproposetomonitorTcellsusing innovativetechnologiesin:(1)eachofthecohortsproposedinProject1(i.e.,multi-FAparticipants(n=60) treatedwithmulti-OIT+/-omalizumabordupilumabwhodevelopD[definedasapositivefoodchallenge reactionaftera6weekwithdrawalofOIT]vs.SU[definedasanegativefoodchallengereactionafter withdrawalofOIT]totherespectiveallergensintheirmulti-OIT);?(2)longtermfollowupstudiesof>240 participantsonOIT;?and(3)GIbiopsiesobtainedovertimeinOITparticipants).InProject3,wewill investigatewhetherchangesinparticipants?Tcellsubpopulationscanidentifymarkerspredictiveofclinical outcomes.Weparticularlywillfocusonchangesinallergen-specificTh2cellsinthosewhoexhibitfavorable responsestoOIT.BycharacterizingandquantifyingthemodulationofTcellphenotypeandfunction associatedwithvariousmulti-OIToutcomes,wewillidentifyTcellsignaturesofSUinmulti-FAparticipants. Ourmainhypothesesarethatsuccessfulmulti-OITwill:(1)reprogramtotalandallergen-specificTh2cells toTh1and/orTregsubtype,(2)replaceallergen-specificTh2cellsbyTh1andTregsubtype,and/or(3) expandallergen-specificcloneswithdiversephenotypeandfunction,potentiallyoverridingtheeffectsof Th2cells.WespeculatethatstableepigeneticchangesinIL4,IL10,IFN?and/orFOXP3genesmediatethe anticipatedshiftfromTh2phenotype,contributingtoSU.Totestthesehypotheses,weproposeto:
(Aim1) Characterizetheimmunophenotypicandfunctionalchangesinducedbymulti-OITintotalandallergen- specificTcells;?(Aim2)UseMHCclassIImultimerstosortallergen-(peanut/milk/cashew)specificsingle cellsandperformtargetedRNA-seqtoinvestigatetheirmolecularsignaturesandclonalancestryatsingle cellresolution;?and(Aim3)Quantifyepigeneticchanges(i.e.,methylationofCpGislands)inkeygenes (i.e.,FOXP3,IL4,IFN?,IL10)toassesspossiblelinksbetweengenemethylation,andthusexpressionof thesegenes,andfavorableOITclinicaloutcomes.Ifweachievetheseaims,weexpectourresultswillboth providenewinsightsintothemechanismsunderlyingsuccessfulclinicaloutcomesinmulti-OITandimprove understandingoftheimmunechangesthatcancontributetosuccessfuloutcomesinOIT.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI104209-07
Application #
9851800
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2020-02-01
Budget End
2021-01-31
Support Year
7
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Stanford University
Department
Type
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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
Klein, Ofir; Roded, Amit; Hirschberg, Koret et al. (2018) Imaging FITC-dextran as a Reporter for Regulated Exocytosis. J Vis Exp :
Zhang, Wenming; Lin, Chunrong; Sampath, Vanitha et al. (2018) Impact of allergen immunotherapy in allergic asthma. Immunotherapy 10:579-593
Sampath, Vanitha; Sindher, Sayantani B; Zhang, Wenming et al. (2018) New treatment directions in food allergy. Ann Allergy Asthma Immunol 120:254-262
Sindher, Sayantani B; Long, Andrew; Acharya, Swati et al. (2018) The Use of Biomarkers to Predict Aero-Allergen and Food Immunotherapy Responses. Clin Rev Allergy Immunol 55:190-204
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

Showing the most recent 10 out of 53 publications