Abstract

Foodallergies(FAs)areaworld-wideproblem,andallergiestomultiplefoodsareparticularlyproblematic.In theU.S.,ingestionofoffendingfoodallergensisthemostcommoncauseofanaphylaxisseeninhospital emergencydepartments(EDs),anditisestimatedthat~30,000food-inducedanaphylacticeventsareseenin U.S.EDseachyear;?sadly,~200oftheseeventsprovefatal.Peanutsortreenutscausethemajorityofthese deaths,andarecentsurveyintheU.S.foundthat1.4%ofthepopulationisallergictopeanutsortreenutsand ~30%ofpatientswithFAshaveallergiestomultiplefoods.Inpeanutallergy(PA),landmarkstudiesbyA. WesleyBurksandcolleagueshaveshownthatchildrencanbedesensitizedtopeanutviaanoral immunotherapy(OIT)protocol.Wehavereplicatedtheseresultsinadultsandchildren,andalsohavecarried outapilotstudyshowingthatFApatientscanbedesensitizedtomultiplefoodallergenssimultaneously(i.e., multi-OIT).Moreover,wefoundthattherewerefeweradverseeventsinthebuild-upphaseofmulti-OITif patientsreceivedtheanti-IgEantibody,omalizumab,concomitantlywithmulti-OIT. Inanefforttoimproveunderstandingofthesystemicandlocal(i.e.,GI)immuneresponsesthatunderliePA andtherapeuticresponsestoOIT,wearecurrentlyconductingaplacebo-controlled,randomized,phase2 clinicaltrialofOITin120childrenandadultswithPA(thePOISEDtrial),andareapplyingstate-of-the-art humanimmunemonitoringmethodstoanalyzebloodandGItissuespecimensofparticipantsinthatstudy.In thisAADCRCU19renewalapplication,weproposetoconductapilot,placebo-controlled,randomized,phase 2clinicaltrialofOITwithorwithoutomalizumabortheanti-IL-4R?antibody,dupilumab,inchildrenandadults withmultipleFAs(multi-FAs).WeproposetomeasureabroadrangeofbloodandGIbiopsycellularfindings, aswellasserologicandclinicalfindings,inlongitudinalsamplesfrommulti-FAparticipantsundergoingthetrial, aswellasfromappropriatecontrolparticipants(i.e.,multi-FAparticipantswhoarenottreated,healthycontrols, andatopiccontrolswithoutFA).WewillusethesedatatodefinehowkeysystemicorGItissueimmune parameterschangeduringmulti-OIT,andwhicharemostpredictiveofthenatureanddurabilityofpatient responsestothistherapy.Specifically,wewillevaluatewhetherthereareblood-orGItissue-derived biomarkersthatpredicttherapeuticresponsestoindividualallergens,ortoallallergens,inmulti-OIT.In addition,wewillseektoidentifyimmunemonitoringparameters,includingfindingsderivedfromanalysesof basophilphenotypeandfunctionthatcanberapidlyperformedinaclinicallaboratoryusingsmallamountsof blood,thatcouldbeusedtopredicttheclinicalreactivitytooffendingallergensinmulti-FAsubjects,toimprove thesafetyandefficacyofOITprotocols,and/ortotailortheOITprotocoltoeachindividualsubject.

Public Health Relevance

Foodallergy(FA)tomultiplefoodsisincreasinglycommonandcancauseseriousillnessanddeathinchildren andadults.WewilluseinnovativeapproachesforimmunemonitoringanddataanalysisofbloodandGI tissuestoinvestigatefactorsresponsibleforFA,andtoimproveourabilitytomanipulatetheimmunesystemto safelytreatpeoplewithFAs.Wewillalsotrytodeveloprapidbloodteststhatcanbeusedtotailortreatment foreachindividualpatientwithFAtoimprovetreatmentsafetyandefficacy.

  Funding Agency

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 #
9851783
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Dong, Gang
Project Start
2013-07-01
Project End
2024-01-31
Budget Start
2020-02-01
Budget End
2021-01-31
Support Year
7
Fiscal Year
2020
Total Cost
Indirect Cost

  Institution

Name
Stanford University
Department
Pathology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305

  Publications

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
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

Showing the most recent 10 out of 53 publications