Targeting IL-4/IL-13 signaling to alleviate oral allergen–induced diarrhea
Received 5 August 2008; received in revised form 7 September 2008; accepted 1 October 2008. published online 11 November 2008.
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.
aDivision of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
bDivision of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
cDivision of Immunology, University of Cincinnati College of Medicine, Cincinnati, Ohio
Reprint requests: Marc E. Rothenberg, MD, PhD, Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229.
Supported in part by National Institutes of Health grant AI45898-05, the Campaign Urging Research for Eosinophilic Diseases (CURED), the Food Allergy Project, and the US Department of Veterans Affairs.
Disclosure of potential conflict of interest: F. D. Finkelman has served as a consultant for Amgen and Abbott. M. E. Rothenberg has served as a speaker and consultant for Merck and as a consultant for Ception Therapeutics, Novartis, and Nycomed and has received research support from the National Institutes of Health, the Food Allergy and Anaphylaxis Network, and the Dana Foundation. The rest of the authors have declared that they have no conflict of interest.
ABSTRACT