Peanut allergen inhibition prevents anaphylaxis in a humanized mouse model

Abstract

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 γc-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.

Interleukin-9 promotes mast cell progenitor proliferation and CCR2-dependent mast cell migration in allergic airway inflammation

“…We then tested whether our findings are relevant for human MCs by generating humanized NSG-SGM3 mice that develop human MC and intranasally treating these mice with recombinant human IL-9 for 3 days ( Fig. 2H ) 35 . Similar to our findings in murine MC, we demonstrate that intranasal IL-9 enhances MC numbers in the lungs and bone marrow ( Figs.…”

“…6B ). We measured known human MC degranulation markers taken one hour after antigen challenge 35 , 43 . Transfer of mMC led to greater MC degranulation marker expression of MCPT1, IL-6, and CCL2 as compared to PBS transfer controls ( Supplementary Fig.…”

Allergenicity and Linear Epitope Analysis of Scy p 8, an Allergen from Mud Crab

“…The allergenicity of an allergen primarily depends on epitopes, encompassing linear and conformational IgE binding epitopes, which play a crucial role in triggering an allergic response . The investigation into allergen IgE epitopes, which enhances the overall comprehension of allergens holds potential for clinical applications of food allergies. , Various experimental techniques are available for the determination of IgE epitopes; however, they often incur high costs, require significant time investment, and demand a substantial level of laboratory expertise. Over the past few decades, a range of computational techniques, mostly founded on machine learning methodologies have been developed to address this complex challenge .…”

Immunoglobulin E Epitope Mapping and Structure–Allergenicity Relationship Analysis of Crab Allergen Scy p 9

“…21 The study of allergen IgE epitopes would not only help to enrich the comprehensive understanding of allergens but also help to diagnose and treat food allergy in the clinical environment. 22,23 Because of the rapid development of computer informatics and molecular biology, the combination of the two research methods had gradually become the mainstream. 9, 24 Huan et al 18 utilized bioinformatics combined with peptide synthesis technology in oysters to validate the nine IgE linear epitopes of AK through serological experiments.…”

“…They are generally located on the surface of antigen molecules to facilitate direct contact with antibodies or cell surface receptors . The study of allergen IgE epitopes would not only help to enrich the comprehensive understanding of allergens but also help to diagnose and treat food allergy in the clinical environment. , Because of the rapid development of computer informatics and molecular biology, the combination of the two research methods had gradually become the mainstream. , Huan et al utilized bioinformatics combined with peptide synthesis technology in oysters to validate the nine IgE linear epitopes of AK through serological experiments. Chen et al verified the conformational epitope by mutating the critical amino acid in the conformational epitope predicted by SCP into alanine and observing the changes in the IgG-/IgE-binding capacity of the mutant.…”