Immunotherapy-induced neutralizing antibodies disrupt allergen binding and sustain allergen tolerance in peanut allergy

LaHood, Nicole A.; Min, Jungki; Keswani, Tarun; Richardson, Crystal M.; Amoako, Kwasi; Zhou, Jingjia; Marini-Rapoport, Orlee; Bernard, Hervé; Hazebrouck, Stéphane; Shreffler, Wayne G.; Love, J. Christopher; Pomes, Anna; Pedersen, Lars C.; Mueller, Geoffrey A.; Patil, Sarita U.

doi:10.1172/jci164501

Immunotherapy-induced neutralizing antibodies disrupt allergen binding and sustain allergen tolerance in peanut allergy

Journal Article · Tue Jan 17 00:00:00 EST 2023 · Journal of Clinical Investigation

DOI:https://doi.org/10.1172/jci164501· OSTI ID:2423466

LaHood, Nicole A. ^[1]; ^[2]; ^[1]; Richardson, Crystal M. ^[3]; ^[1]; Zhou, Jingjia ^[1]; Marini-Rapoport, Orlee ^[4]; Bernard, Hervé ^[5]; ^[5]; Shreffler, Wayne G. ^[1]; ^[6]; Pomes, Anna ^[3]; ^[2]; ^[2]; ^[1]

Massachusetts General Hospital, Boston, MA (United States)
National Institute of Environmental Health Sciences, Research Triangle Park, NC (United States)
InBio, Charlottesville, VA (United States)
Harvard Univ., Cambridge, MA (United States)
Univ. Paris-Saclay, Gif-sur-Yvette (France)
Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States). Koch Institute for Integrative Cancer Research

In IgE-mediated food allergies, exposure to the allergen activates systemic allergic responses. Oral immunotherapy (OIT) treats food allergies through incremental increases in oral allergen exposure. However, OIT only induces sustained clinical tolerance and decreased basophil sensitivity in a subset of individuals despite increases in circulating allergen-specific IgG in all treated individuals. Therefore, we examined the allergen-specific antibodies from 2 OIT cohorts of patients with sustained and transient responses. Here, we compared antibodies from individuals with sustained or transient responses and discovered specific tolerance-associated conformational epitopes of the immunodominant allergen Ara h 2 recognized by neutralizing antibodies. First, we identified what we believe to be previously unknown conformational, intrahelical epitopes using x-ray crystallography with recombinant antibodies. We then identified epitopes only recognized in sustained tolerance. Finally, antibodies recognizing tolerance-associated epitopes effectively neutralized allergen to suppress IgE-mediated effector cell activation. Our results demonstrate the molecular basis of antibody-mediated protection in IgE-mediated food allergy, by defining how these antibodies disrupt IgE-allergen interactions to prevent allergic reactions. Our approach to studying the structural and functional basis for neutralizing antibodies demonstrates the clinical relevance of specific antibody clones in antibody-mediated tolerance. We anticipate that our findings will form the foundation for treatments of peanut allergy using neutralizing antibodies and hypoallergens.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 2423466

Journal Information:: Journal of Clinical Investigation, Journal Name: Journal of Clinical Investigation Journal Issue: 2 Vol. 133; ISSN 1558-8238

Publisher:: American Society for Clinical InvestigationCopyright Statement

Country of Publication:: United States

Language:: English

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