Targeting IL-4/IL-13 signaling to alleviate oral allergen-induced diarrhea

Background: Intestinal anaphylaxis (manifested by acute diarrhea) is dependent on IgE and mast cells. Objective: We aimed to define the respective roles of IL-4 and IL-13 and their receptors in disease pathogenesis. Methods: Wild-type mice and mice deficient in IL-4, IL-13, and IL-13 receptor (IL-13R) α1 (part of the type 2 IL-4 receptor [IL-4R]) were sensitized with ovalbumin (OVA)/aluminum potassium sulfate and subsequently given repeated intragastric OVA exposures. The IL-4Rα chain was targeted with anti-IL-4Rα mAb before or after intragastric OVA exposures. Results: IL4^-/- (and IL4/IL13^-/-) mice produced almost no IgE and were highly resistant to OVA-induced diarrhea, whereas allergic diarrhea was only partially impaired in IL13^-/- and IL13Rα1^-/- mice. IL13Rα1-deficient mice had decreased IgE levels, despite having normal baseline IL-4 levels. Intestinal mast cell accumulation and activation also depended mainly on IL-4 and, to a lesser extent, on IL-13. Prophylactic anti-IL-4Rα mAb treatment, which blocks all IL-4 and IL-13 signaling, suppressed development of allergic diarrhea. However, treatment with anti-IL-4Rα mAb for 7 days only partially suppressed IgE and did not prevent intestinal diarrhea. Conclusion: Endogenously produced IL-13 supplements the ability of IL-4 to induce allergic diarrhea by promoting oral allergen sensitization rather than the effector phase of intestinal anaphylaxis.