An Antagonistic IL-4 Mutant Prevents Type I Allergy in the Mouse: Inhibition of the IL-4/IL-13 Receptor System Completely Abrogates Humoral Immune Response to Allergen and Development of Allergic Symptoms In Vivo

We have analyzed in vivo effects of the murine IL-4 mutant Q116D/Y119D (QY), which forms unproductive complexes with IL-4Ralpha and is an antagonist for IL-4 and IL-13 in vitro. Treatment of BALB/c mice with QY during immunization with OVA completely inhibited synthesis of OVA-specific IgE and IgG1....

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Bibliographic Details
Published in:The Journal of immunology (1950) 1998-04, Vol.160 (8), p.4004-4009
Main Authors: Grunewald, Susanne M, Werthmann, Antje, Schnarr, Bernd, Klein, C. Eberhard, Brocker, Eva B, Mohrs, Markus, Brombacher, Frank, Sebald, Walter, Duschl, Albert
Format: Article
Language:English
Subjects:
Allergens - administration & dosage
Anaphylaxis - prevention & control
Animals
Antibody Formation
Female
Hypersensitivity, Immediate - prevention & control
Immunoglobulin E - biosynthesis
Immunoglobulin G - biosynthesis
Interleukin-13 Receptor alpha1 Subunit
Interleukin-4 - genetics
Mice
Mice, Inbred BALB C
Mice, Knockout
Mutation
Ovalbumin - immunology
Receptors, Interleukin - antagonists & inhibitors
Receptors, Interleukin-13
Receptors, Interleukin-4 - antagonists & inhibitors
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Summary:We have analyzed in vivo effects of the murine IL-4 mutant Q116D/Y119D (QY), which forms unproductive complexes with IL-4Ralpha and is an antagonist for IL-4 and IL-13 in vitro. Treatment of BALB/c mice with QY during immunization with OVA completely inhibited synthesis of OVA-specific IgE and IgG1. BALB/c-derived knockout mice lacking either IL-4 or IL-4Ralpha also did not develop specific IgE or IgG1, but mounted a much stronger IgG2a and IgG2b response than wild-type mice. In contrast, QY treatment of normal BALB/c mice suppressed specific IgG2a, IgG2b, and IgG3 synthesis, which may indicate the development of tolerance toward the allergen. Associated with the lack of IgE synthesis in QY-treated wild-type mice and in IL-4(-/-) mice used as a control was the failure to develop immediate cutaneous hypersensitivity or anaphylactic shock upon rechallenge. Interestingly, QY treatment also inhibited humoral immune responses and allergic reactivity in SJL/J mice, a strain that did not produce IgE, but displayed IgE-independent mast cell degranulation mediated by specific IgG1. We conclude that QY inhibits Ag-specific humoral immune responses and allergic symptoms mediated either by IgE or IgG1. It needs to be clarified how QY abrogates synthesis of IgG2a, IgG2b, and IgG3, but the induction of tolerance toward nonhazardous protein Ags should be advantageous for therapy of atopic disorders and other Th2-dominated diseases.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.160.8.4004