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Principal Investigator: Hans C Oettgen
Organization: BOSTON CHILDREN'S HOSPITAL
Fiscal Year: 2024
Award: $598,688
Funding agency: National Institute of Allergy and Infectious Diseases
While food allergy has emerged as a major health issue, treatment options are quite limited. There is an
urgent need to identify the specific environmental and endogenous factors that prime and then sustain allergic
responses to foods so that new mechanism-based therapies can be developed. We have found that, IgE-
activated mast cells, best known for causing immediate hypersensitivity reactions including food anaphylaxis,
actually play a separate but critical role as food allergen sensors and adjuvants for Type 2 immune responses
and that the activating effects of food-specific IgE on mast cells can be countered by IgG antibodies of
corresponding specificity. Important questions remain unanswered, however: 1) What specific aspects of
Type 2 immunity (Th2, ILC2, IgE+ B cells) are enhanced by IgE-activated mast cells?, 2) Are these effects
mediated by mast cell cytokines?, 3) Is the protective effect of IgG antibodies in vivo, suppressing Th2 and
enhancing Treg responses, mediated by their negative signals, delivered via FcgR2b, specifically in mast cells
and can responses to food allergens be attenuated by using specific monoclonal IgG antibodies to activate this
suppressive pathway? These questions will be answered in this project under the following aims:
AIM 1: Establish how IgE-activated mast cells promote food allergy:
1.1 Test the impact of IgE-activated mast cells in vivo on emergence of Th2, Tfh and IgE+ B cells and
evaluate the contributions of mast cell derived Th2 cytokines
1.2 Examine mast cell effects on emerging effector RORgt+ vs. pathogenic GATA-3+, IRF-4+, IL-4+ Treg
1.3 Evaluate reciprocal TGFb-mediated inhibitory effects of Treg on mast cell functions
1.4 Examine the influence of IgE-activated mast cells on ILC2 induction in vivo: Roles of mast cell- vs. gut
epithelial cell-derived cytokines
AIM 2: Determine how IgG:FcgR2b signals can reset the immune response in food allergy:
2.1 Evaluate the direct role of IgG inhibitory signals in mast cells in suppression of Type 2 and restoration
of functional Treg responses in food allergy
2.2 Evaluate the effects of high-affinity human monoclonal peanut specific IgG antibodies (and their IgG
subclass swap variants) cloned from single B cells transcriptomes on IgE-mediated basophil activation
2.3 Use our humanized mouse model of peanut allergy to test the effects of monoclonal peanut-specific
IgE on immediate hypersensitivity responses (systemic anaphylaxis).
2.4 Test IgG effects on Th, Tfh and Treg responses in the humanized mice
Terms: <0-11 years old><7S Gamma Globulin><Adjuvant><Affect><Affinity><Allergens><Allergic><Allergic to food><Allergy to food><Allergy to peanuts><Anaphylactic Reaction><Anaphylactic Shock><Anaphylaxis><Animals><Antibodies><Atopic Hypersensitivity><Attenuated><B blood cells><B cell><B cell growth factor><B cells><B-Cell Differentiation Factor-1><B-Cell Growth Factor-1><B-Cell Growth Factor-I><B-Cell Proliferating Factor><B-Cell Stimulating Factor><B-Cell Stimulating Factor-1><B-Cell Stimulation Factor-1><B-Cell Stimulatory Factor-1><B-Cells><B-Lymphocytes><B-cell><BCDF-1><BCGF><BCGF-1><BCSF 1><BSF-1><BSF1><Basophilic Granulocyte><Basophils><Binetrakin><Blood Basophil><Cell Body><Cell Communication and Signaling><Cell Function><Cell Physiology><Cell Process><Cell Signaling><Cells><Cellular Function><Cellular Physiology><Cellular Process><Child><Child Youth><Children (0-21)><Clinical Treatment Moab><Developed Countries><Development><Endogenous Factors><Enterocytes><Environmental Factor><Environmental Risk Factor><Epithelial Cells><Equilibrium><Family><Fc Receptor><Food><Food Allergy><Food Hypersensitivity><Fostering><Groundnut Hypersensitivity><Gut Epithelium><Health><Hu-mABs><IL-4><IL4 Protein><IgE><IgE-Mediated Hypersensitivity><IgG><Immediate hypersensitivity><Immune><Immune response><Immunes><Immunity><Immunochemical Immunologic><Immunoglobulin E><Immunoglobulin G><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><Immunomodulation><Impairment><Industrialized Countries><Industrialized Nations><Ingestion><Interleukin-4><Interleukin-4 Precursor><Intestinal><Intestines><Intracellular Communication and Signaling><Lymphocyte Stimulatory Factor 1><MCGF-2><Marrow Mast Cell><Mast Cell Growth Factor-2><Mediating><Mice><Mice Mammals><Modeling><Monoclonal Antibodies><Murine><Mus><Pathogenicity><Pathway interactions><Patients><Peanut Hypersensitivity><Play><Prevalence><Probability><Reaction><Regulation><Regulatory T-Lymphocyte><Role><Signal Induction><Signal Transduction><Signal Transduction Systems><Signaling><Specificity><Subcellular Process><T-Cell Growth Factor 2><T-Cells><T-Lymphocyte><Teff cell><Testing><Th-2 Cell><Th2 Cells><Tissue Basophils><Treg><Type 2 Helper Cell><Type I Hypersensitivity><Variant><Variation><Work><allergen response><allergic response><allergic to peanuts><allergy response><antibody receptor><attenuate><attenuates><balance><balance function><biological signal transduction><bowel><cytokine><developed country><developed nation><developed nations><developmental><effector T cell><environmental risk><food allergen><food protection><food supply protection><functional restoration><gastrointestinal epithelium><global gene expression><global transcription profile><host response><humAbs><human mAbs><human monoclonal antibodies><human monoclonals><humanized mice><humanized mouse><humoral hypersensitivity><immune modulation><immune regulation><immune system response><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><in vivo><ingest><inhibitor><kids><mAbs><mast cell><mastocyte><monoclonal Abs><mouse model><murine model><oral immunotherapy><pathway><peanut allergy><promoter><promotor><protective effect><regulatory T-cells><response><restore function><restore functionality><restore lost function><sensor><social role><therapeutic target><thymus derived lymphocyte><transcriptome><villin><youngster>