Eric B. Brandt, PhD, Ariel Munitz, PhD, Tatyana Orekov, MS, Melissa K

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Targeting IL-4/IL-13 signaling to alleviate oral allergen–induced diarrhea Eric B. Brandt, PhD, Ariel Munitz, PhD, Tatyana Orekov, MS, Melissa K. Mingler, MS, Melissa McBride, BS, Fred D. Finkelman, MD, Marc E. Rothenberg, MD, PhD Journal of Allergy and Clinical Immunology Volume 123, Issue 1, Pages 53-58 (January 2009) DOI: 10.1016/j.jaci.2008.10.001 Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Ablated intestinal anaphylaxis in the absence of IL-4 and IL-13. A, Protocol timeline. B, Occurrence of diarrhea was assessed in OVA/alum-primed wild type, IL-13−/−, IL-4/13−/−, and IL-4−/− mice (n = 9-14 mice per group) up to 60 minutes after each intragastric inoculation with 50 mg of OVA. D, Jejunum mast cell numbers were assessed by means of morphometric analysis of chloroacetate esterase–stained cells. C and E, IgE (Fig 1, C) and MMCP1 (Fig 1, E) levels were measured by means of ELISA in blood drawn 60 to 90 minutes after the last saline or OVA inoculation. Serum IgE and MMCP1 levels were 490 ± 204 ng/mL and 9.7 ± 7.8 pg/mL, respectively, in naive wild-type mice, which had 35 ± 25 mast cells/mm3 of jejunum. i.p., Intraperitoneal; WT, wild-type; Sal, saline; n.s., not significant. ∗∗P < .01, ∗∗∗P < .001. Journal of Allergy and Clinical Immunology 2009 123, 53-58DOI: (10.1016/j.jaci.2008.10.001) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 IL-13 contributes to IgE and mast cell allergic responses. A, Diarrhea occurrences in OVA/alum–primed wild-type and IL-13Rα1−/− mice after 1 to 6 intragastric inoculations with 10 mg of OVA. B-D, Serum IgE levels (Fig 2, B), jejunum mast cell numbers (Fig 2, C), and serum MMCP1 levels (Fig 2, D) were compared in wild-type and IL-13Rα1–deficient mice (7-18 per group). WT, Wild-type; KO, knockout. ∗∗P < .01. Journal of Allergy and Clinical Immunology 2009 123, 53-58DOI: (10.1016/j.jaci.2008.10.001) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Prophylactic effects of anti-IL-4Rα mAb. OVA/alum-primed BALB/c mice (5 per group) were injected intraperitoneally with either 2 mg of 4-3 anti-IL-4Rα mAb or a control IgG1 mAb 1 day before the first intragastric inoculation with OVA. A, Development of diarrhea was assessed during the 60 minutes after each intragastric OVA inoculation. B, Representative jejunum section of antibody-treated mice stained with chloroacetate esterase. C, Intestinal mast cell numbers were assessed by means of morphometric analysis. D and E, Blood MMCP1 (Fig 3, D) and total IgE (Fig 3, E) levels were assessed 1 to 2 hours after the last allergen exposure. i.g., Intragastric; Ab, antibody; Ctl, control. ∗∗P < .01. Journal of Allergy and Clinical Immunology 2009 123, 53-58DOI: (10.1016/j.jaci.2008.10.001) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 IL-4 and IL-13 are not required during the effector phase of allergic diarrhea. A, Once diarrhea had developed (after 4 intragastric challenges with OVA), BALB/c mice (6 per group) were injected with 2 mg of 4-3 or control IgG1 mAb before the fifth, sixth, and seventh OVA inoculations (n = 6 mice per group). B, One week and 3 OVA inoculations later, mice were killed, and plasma IgE levels were determined. C and D, Jejunum mast cell numbers (Fig 4, C) and MMCP1 blood levels (Fig 4, D) were assessed 1 to 2 hours after the last OVA inoculation. Ab, Antibody; Ctl, control; i.v., intravenous; i.p., intraperitoneal; i.g., intragastric. ∗P < .05, ∗∗P < .01. Journal of Allergy and Clinical Immunology 2009 123, 53-58DOI: (10.1016/j.jaci.2008.10.001) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions