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) alpha1 (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-4R alpha chain was targeted with anti-IL-4R alpha 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 IL13Ralpha1(-/-) mice. IL13Ralpha1-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-4R alpha mAb treatment, which blocks all IL-4 and IL-13 signaling, suppressed development of allergic diarrhea. However, treatment with anti-IL-4R alpha mAb for 7 days only partially suppressed IgE and did not prevent intestinal diarrhea.


CONCLUSIONS
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.
Brandt
Eric B
EB
Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
Munitz
Ariel
A
Orekov
Tatyana
T
Mingler
Melissa K
MK
McBride
Melissa
M
Finkelman
Fred D
FD
Rothenberg
Marc E
ME
D000707:Anaphylaxis / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D003967:Diarrhea / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics / Q000276:immunology; D007073:Immunoglobulin E / Q000276:immunology; D018793:Interleukin-13 / Q000235:genetics / Q000276:immunology*; D053661:Interleukin-13 Receptor alpha1 Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D053662:Interleukin-4 Receptor alpha Subunit
D000911:Antibodies, Monoclonal; D007073:Immunoglobulin E; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D015847:Interleukin-4; D011956:Receptors, Cell Surface; C508183:Il13ra1 protein, mouse; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit