Blockade of peanut allergy with a novel Ara h 2–Fcγ fusion protein in mice Yu Liu, MD, PhD, Yongtao Sun, MD, PhD, Lee-Jah Chang, MD, Newton Li, MD, Huabin.

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Presentation transcript:

Blockade of peanut allergy with a novel Ara h 2–Fcγ fusion protein in mice Yu Liu, MD, PhD, Yongtao Sun, MD, PhD, Lee-Jah Chang, MD, Newton Li, MD, Huabin Li, MD, PhD, Yanni Yu, BSc, Paul J. Bryce, PhD, Leslie C. Grammer, MD, Robert P. Schleimer, PhD, Daocheng Zhu, MD, PhD Journal of Allergy and Clinical Immunology Volume 131, Issue 1, Pages 213-221.e5 (January 2013) DOI: 10.1016/j.jaci.2012.10.018 Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Diagram of AHG2-induced inhibition. A, Computerized 3-dimensional structure of dimerized AHG2. B, Proposed mechanism by which AHG2 inhibits FcεRI-meditated degranulation. ITAM, Immunoreceptor tyrosine-based activation motif; ITIM, immunoreceptor tyrosine-based inhibitory motif; MAPK, mitogen-activated protein kinase; PI3K, phosphoinositide 3-kinase; PLC, phospholipase C; SHIP, Src homology domain 2–containing inositol phosphatase; Syk, spleen tyrosine kinase. Journal of Allergy and Clinical Immunology 2013 131, 213-221.e5DOI: (10.1016/j.jaci.2012.10.018) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Characterization of AHG2 fusion protein. A, AHG2 was confirmed by using Western blotting and probed with antibodies specific for human IgG Fc and Ara h 2. B, AHG2 was recognized based on peanut-specific IgE. C, AHG2 bound to FcγRIIb expressed on HMC-1 cells. FITC, Fluorescein isothiocyanate; SSC, side scatter. Journal of Allergy and Clinical Immunology 2013 131, 213-221.e5DOI: (10.1016/j.jaci.2012.10.018) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 AHG2 blocked Ara h 2–induced vascular leak in transgenic mice. A, WPE induced peanut-specific IgE-mediated PCA in transgenic mice. NS, Nonallergic serum; PS, serum from a patient with peanut allergy. B, Ara h 2 induced PCA meditated by different concentrations of peanut-specific IgE from serum from a patient with peanut allergy. PS, Serum from a patient with peanut allergy; 1:1PS, 1:1 dilution of serum; 1:5PS, 1:5 dilution of serum; 1:10PS, 1:10 dilution of serum. C, AHG2 did not induce peanut-specific IgE-mediated PCA in transgenic mice. D, AHG2 inhibited Ara h 2–induced, peanut-specific IgE-mediated PCA in a dose-dependent manner. PS, Serum from a patient with peanut allergy; PS-0.1, serum with 0.1 μg of AHG2; PS-1, serum with 1 μg of AHG2; PS-10, serum with 10 μg of AHG2. Each experiment was repeated with 3 transgenic mice. Journal of Allergy and Clinical Immunology 2013 131, 213-221.e5DOI: (10.1016/j.jaci.2012.10.018) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 AHG2 inhibited WPE-induced allergic reactions in vitro and in vivo. A, AHG2 inhibited WPE-induced histamine release in human basophils. Results are representative of 3 separate experiments, each done in duplicate. B, AHG2 inhibited the peanut-specific IgE-mediated PCA reaction in a dose-dependent manner. C, The average blue density of 5 mice for each of the above tests. PS, Serum from a patient with peanut allergy; PS-0.01, serum with 0.01 μg of AHG2; PS-0.1, serum with 0.1 μg of AHG2; PS-1, serum with 1 μg of AHG2. Journal of Allergy and Clinical Immunology 2013 131, 213-221.e5DOI: (10.1016/j.jaci.2012.10.018) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 AHG2 inhibited systemic anaphylaxis caused by the peanut extract in mice. Four groups of mice were sensitized with the peanut antigen. Group 1 (n = 5) was a control, group 2 (n = 9) was challenged with WPE, group 3 (n = 9) was treated with 1 mg/kg AHG2 (AHG2-L) and then challenged with WPE, and group 4 (n = 9) was treated with 10 mg/kg AHG2 (AHG2-H) and then challenged with WPE. Each mouse was evaluated for their symptoms score (A), body temperature (B), and histamine level in blood (C). Data are representative of 2 separate experiments. *P < .05. Journal of Allergy and Clinical Immunology 2013 131, 213-221.e5DOI: (10.1016/j.jaci.2012.10.018) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 AHG2 lost its inhibitory effect in FcγRIIb-deficient mice. Three groups of FcγRIIb knockout mice were sensitized and challenged with WPE. Group 1 (n = 6) was a control challenged with saline, group 2 (n = 6) was not treated with AHG2, and group 3 (n = 7) was treated with 10 mg/kg AHG2 before WPE challenge. Each mouse was evaluated for their symptoms score (A) and body temperature (B). Data are representative of 2 separate experiments. Journal of Allergy and Clinical Immunology 2013 131, 213-221.e5DOI: (10.1016/j.jaci.2012.10.018) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 AHG2 inhibited WPE-induced inflammation in the airways of WPE-sensitized mice. A, Differential cell counts in bronchoalveolar lavage fluid. The bronchoalveolar lavage fluid was collected from each mouse of the above groups. The results are representative of the average of each group. *P < .05. B, Histologic airway changes. Representative histologic sections of lung tissues from the mice in Fig 5 were stained with hematoxylin and eosin. Bar = 100 μm. Journal of Allergy and Clinical Immunology 2013 131, 213-221.e5DOI: (10.1016/j.jaci.2012.10.018) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 AHG2 fusion protein was recognized by peanut-specific IgE from serum from a patient with peanut allergy (no. 15815). M, Molecular weight. Journal of Allergy and Clinical Immunology 2013 131, 213-221.e5DOI: (10.1016/j.jaci.2012.10.018) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Serum levels of specific IgE to WPE and the peanut components in 3 patients with peanut allergy. Journal of Allergy and Clinical Immunology 2013 131, 213-221.e5DOI: (10.1016/j.jaci.2012.10.018) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 AHG2 inhibited histamine release in RBL-2H3 cells transfected with human FcεRIα and FcγRIIb. Journal of Allergy and Clinical Immunology 2013 131, 213-221.e5DOI: (10.1016/j.jaci.2012.10.018) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 AHG2 inhibited PCA reaction in transgenic mice sensitized with patients' sera no. 17019 (A) and no. 18885 (B). PS, Serum from a patient with peanut allergy; PS-0.01, serum with 0.01 μg of AHG2; PS-0.1, serum with 0.1 μg of AHG2; PS-1, serum with 1 μg of AHG2. Journal of Allergy and Clinical Immunology 2013 131, 213-221.e5DOI: (10.1016/j.jaci.2012.10.018) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 AHG2 inhibited systemic anaphylaxis caused by the peanut extract in the sensitized mice. After challenge with WPE, the sensitized mice were randomly divided into 2 groups: one group (n = 8) was treated with our AHG2 protein, and the other (n = 8) was treated with PBS as a control. After treatment, all mice were intraperitoneally challenged again with WPE. Each mouse was evaluated in terms of symptoms (A), and body temperature was measured (B). Journal of Allergy and Clinical Immunology 2013 131, 213-221.e5DOI: (10.1016/j.jaci.2012.10.018) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions