Allergen-induced IgE-dependent gut inflammation in a human PBMC–engrafted murine model of allergy Benno Weigmann, PhD, Nadja Schughart, MSc, Christian.

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Allergen-induced IgE-dependent gut inflammation in a human PBMC–engrafted murine model of allergy Benno Weigmann, PhD, Nadja Schughart, MSc, Christian Wiebe, MD, Stephan Sudowe, PhD, Hans A. Lehr, MD, Helmut Jonuleit, PhD, Lothar Vogel, PhD, Christoph Becker, PhD, Markus F. Neurath, MD, Stephan Grabbe, MD, Joachim Saloga, MD, Iris Bellinghausen, PhD Journal of Allergy and Clinical Immunology Volume 129, Issue 4, Pages 1126-1135 (April 2012) DOI: 10.1016/j.jaci.2011.11.036 Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Production of human total and allergen-specific IgE in human PBMC–engrafted NOD-scid-γc−/− mice. PBMCs (2 × 107) were injected intraperitoneally with or without the respective allergen, and human IgE levels were measured in murine sera 3 weeks later by using the ImmunoCAP test (A) or β-hexosaminidase activity of FcεRI-transfected RBL cells (B). Shown are means ± SEMs of 9 (8 for Fig 1, B) different experiments. *P ≤ .01 compared with no allergen stimulation. Journal of Allergy and Clinical Immunology 2012 129, 1126-1135DOI: (10.1016/j.jaci.2011.11.036) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Allergen-specific proliferation and cytokine production in human PBMC–engrafted NOD-scid-γc−/− mice. Three weeks after PBMC engraftment, human CD4+ T cells were recovered from spleens and stimulated with autologous unpulsed (DC medium), allergen-pulsed (DC allergen), or tetanus toxoid–pulsed DCs (DC TT) to analyze their proliferation (A) and cytokine production (B). Shown are means ± SEMs of 6 different experiments. *P ≤ .05 compared with DC medium. Journal of Allergy and Clinical Immunology 2012 129, 1126-1135DOI: (10.1016/j.jaci.2011.11.036) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Allergen-specific gut inflammation in human PBMC–engrafted NOD-scid-γc−/− mice. Three weeks after PBMC engraftment, mice were examined with a video miniendoscope before and after rectal (or oral) allergen challenge. A and B, Shown are the endoscopic pictures (Fig 3, A) of a representative result and the means ± SEMs of the endoscopic score (Fig 3, B) of 7 (6) different experiments (3 [2] for healthy donors) with at least 2 mice per group. *P ≤ .01 compared with the “no PBMC” group. §P ≤ .01 compared with the “PBMC allergic” group. C and D, Staining of the colon with hematoxylin and eosin (×200x magnification) or anti-human CD45 (×40 magnification) after rectal challenge. i.p., Intraperitoneal. Journal of Allergy and Clinical Immunology 2012 129, 1126-1135DOI: (10.1016/j.jaci.2011.11.036) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Gut inflammation is mediated by human IgE and the mediators PAF and histamine. NOD-scid-γc−/− mice were treated and challenged as described in Fig 3. Human IgG control and the humanized anti-IgE mAb omalizumab were administered 3 days and 1 hour before rectal allergen challenge. PAF receptor antagonist or H1 and H2 receptor antagonists were administered 1 hour or 30 minutes before challenge. Shown are the endoscopic pictures (A) of 1 representative result and the single values of the endoscopic score (B) of 7 different experiments. Journal of Allergy and Clinical Immunology 2012 129, 1126-1135DOI: (10.1016/j.jaci.2011.11.036) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Depletion of human FcεRI-expressing effector cells prevents allergen-specific gut inflammation. NOD-scid-γc−/− mice were treated with PBMCs or FcεRIα-depleted PBMCs and challenged as described in Fig 3. Anti-human FcεRIα mAb was additionally applied 3 days and 1 day before challenge. A and B, Shown are the endoscopic pictures (Fig 5, A) of 1 representative result and the single values of the endoscopic score (Fig 5, B) of 5 different experiments. C, Staining of the colon with hematoxylin and eosin (×200 magnification). Journal of Allergy and Clinical Immunology 2012 129, 1126-1135DOI: (10.1016/j.jaci.2011.11.036) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Gut inflammation is prevented by depletion of murine basophils/mast cells but can be restored by addition of human pre-enriched basophils. NOD-scid-γc−/− mice were treated and challenged as described in Fig 3. Anti-mouse FcεRIα mAb or hamster IgG control was administered 6 to 4 days, and pre-enriched human basophils were administered 4 days before challenge. A, One representative staining of murine blood before and after depletion. B, The single values of the percentage of anti-human CD45−, anti-mouse CD117+/FcεRI+ cells in pooled spleens of 7 different experiments. C, Giemsa staining of murine mast cells in the gut (×400 magnification). D and E, Endoscopic pictures of 1 representative result and the single values of the endoscopic score of 8 different experiments. F, One representative staining of human pre-enriched basophils. FITC, Fluorescein isothiocyanate. Journal of Allergy and Clinical Immunology 2012 129, 1126-1135DOI: (10.1016/j.jaci.2011.11.036) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions