PMID- 36753563 OWN - NLM STAT- MEDLINE DCOM- 20230210 LR - 20240211 IS - 1946-6242 (Electronic) IS - 1946-6234 (Print) IS - 1946-6234 (Linking) VI - 15 IP - 682 DP - 2023 Feb 8 TI - Peanut allergen inhibition prevents anaphylaxis in a humanized mouse model. PG - eadd6373 LID - 10.1126/scitranslmed.add6373 [doi] AB - Peanut-induced allergy is an immunoglobulin E (IgE)-mediated type I hypersensitivity reaction that manifests symptoms ranging from local edema to life-threatening anaphylaxis. Although there are treatments for symptoms in patients with allergies resulting from allergen exposure, there are few preventive therapies other than strict dietary avoidance or oral immunotherapy, neither of which are successful in all patients. We have previously designed a covalent heterobivalent inhibitor (cHBI) that binds in an allergen-specific manner as a preventive for allergic reactions. Building on previous in vitro testing, here, we developed a humanized mouse model to test cHBI efficacy in vivo. Nonobese diabetic-severe combined immunodeficient gammac-deficient mice expressing transgenes for human stem cell factor, granulocyte-macrophage colony-stimulating factor, and interleukin-3 developed mature functional human mast cells in multiple tissues and displayed robust anaphylactic reactions when passively sensitized with patient-derived IgE monoclonal antibodies specific for peanut Arachis hypogaea 2 (Ara h 2). The allergic response in humanized mice was IgE dose dependent and was mediated by human mast cells. Using this humanized mouse model, we showed that cHBI prevented allergic reactions for more than 2 weeks when administered before allergen exposure. cHBI also prevented fatal anaphylaxis and attenuated allergic reactions when administered shortly after the onset of symptoms. cHBI impaired mast cell degranulation in vivo in an allergen-specific manner. cHBI rescued the mice from lethal anaphylactic responses during oral Ara h 2 allergen-induced anaphylaxis. Together, these findings suggest that cHBI has the potential to be an effective preventative for peanut-specific allergic responses in patients. FAU - Alakhras, Nada S AU - Alakhras NS AUID- ORCID: 0000-0001-8458-4127 AD - Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202. FAU - Shin, Jaeho AU - Shin J AD - Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, IN 46556, USA. FAU - Smith, Scott A AU - Smith SA AUID- ORCID: 0000-0001-5153-2726 AD - Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA. FAU - Sinn, Anthony L AU - Sinn AL AD - In Vivo Therapeutics Core, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN 46202, USA. FAU - Zhang, Wenwu AU - Zhang W AD - Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. FAU - Hwang, Gyoyeon AU - Hwang G AUID- ORCID: 0000-0002-3335-1136 AD - Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, IN 46556, USA. FAU - Sjoerdsma, Jenna AU - Sjoerdsma J AUID- ORCID: 0000-0003-1506-3330 AD - Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, IN 46556, USA. FAU - Bromley, Emily K AU - Bromley EK AUID- ORCID: 0000-0002-7160-7323 AD - Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, IN 46556, USA. FAU - Pollok, Karen E AU - Pollok KE AUID- ORCID: 0000-0001-6031-5707 AD - In Vivo Therapeutics Core, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN 46202, USA. AD - Department of Pediatrics, HB Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA. FAU - Bilgicer, Basar AU - Bilgicer B AD - Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, IN 46556, USA. FAU - Kaplan, Mark H AU - Kaplan MH AUID- ORCID: 0000-0002-2923-8245 AD - Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202. AD - Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. AD - Department of Pediatrics, HB Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA. LA - eng GR - R01 AI108884/AI/NIAID NIH HHS/United States GR - R01 AI129241/AI/NIAID NIH HHS/United States GR - P20 GM121176/GM/NIGMS NIH HHS/United States GR - U54 DK106846/DK/NIDDK NIH HHS/United States GR - F32 AI088884/AI/NIAID NIH HHS/United States GR - R01 AI028884/AI/NIAID NIH HHS/United States GR - R56 AI129241/AI/NIAID NIH HHS/United States GR - R01 AI155668/AI/NIAID NIH HHS/United States GR - P30 CA082709/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20230208 PL - United States TA - Sci Transl Med JT - Science translational medicine JID - 101505086 RN - 0 (Allergens) RN - 37341-29-0 (Immunoglobulin E) SB - IM MH - Humans MH - Mice MH - Animals MH - *Anaphylaxis/prevention & control MH - Arachis MH - Allergens MH - Immunoglobulin E/metabolism MH - *Peanut Hypersensitivity/prevention & control PMC - PMC10205092 MID - NIHMS1870858 COIS- Competing Interests: B.B. and M.H.K. are owners of IP to commercialize cHBI and similar molecules. EDAT- 2023/02/09 06:00 MHDA- 2023/02/11 06:00 PMCR- 2024/02/08 CRDT- 2023/02/08 14:04 PHST- 2023/02/08 14:04 [entrez] PHST- 2023/02/09 06:00 [pubmed] PHST- 2023/02/11 06:00 [medline] PHST- 2024/02/08 00:00 [pmc-release] AID - 10.1126/scitranslmed.add6373 [doi] PST - ppublish SO - Sci Transl Med. 2023 Feb 8;15(682):eadd6373. doi: 10.1126/scitranslmed.add6373. Epub 2023 Feb 8.