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-4R alpha and is an a ntagonist for IL-4 and IL-13 in vitro, Treatment of BALB/e mice with Q Y during immunization with OVA completely inhibited synthesis of OVA-s pecific IgE and IgG1, BALB/c-derived knockout mice lacking either IL-4 or IL-4R alpha also did not develop specific IgE or IgG1, but mounted a much stronger IgG2a and IgG2b response than wild-type mice, In cont rast, QY treatment of normal BALB/e mice suppressed specific IgG2a, Ig G2b, and IgG3 synthesis, which may indicate the development of toleran ce toward the allergen, Associated with the lack of IgE synthesis in Q Y-treated wild-type mice and in IL-4(-/-) mice used as a control was t he failure to develop immediate cutaneous hypersensitivity or anaphyla ctic shock upon rechallenge, Interestingly, QY treatment also inhibite d humoral immune responses and allergic reactivity in SJL/J mice, a st rain 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 e ither by IgE or IgG1, It needs to be clarified how QY abrogates synthe sis of IgG2a, IgG2b, and IgG3, but the induction of tolerance toward n onhazardous protein Ags should be advantageous for therapy of atopic d isorders and other Th2-dominated diseases.