Although it has long been hypothesized that allergen immunotherapy inhibits
allergy, in part, by inducing production of
IgG Abs that intercept
allergens before they can cross-link mast cell Fc epsilonRI-associated
IgE, this blocking Ab hypothesis has never been tested in vivo. In addition, evidence that
IgG-
allergen interactions can induce
anaphylaxis by activating macrophages through Fc gammaRIII suggested that
IgG Ab might not be able to inhibit
IgE-mediated
anaphylaxis without inducing
anaphylaxis through this alternative pathway. We have studied active and passive immunization models in mice to approach these issues and to determine whether any inhibition of
anaphylaxis observed was a direct effect of
allergen neutralization by
IgG Ab or an indirect effect of cross-linking of Fc epsilonRI to the inhibitory
IgG receptor Fc gammaRIIb. We demonstrate that
IgG Ab produced during the course of an immune response or administered passively can completely suppress
IgE-mediated
anaphylaxis; that these
IgG blocking Abs inhibit
IgE-mediated
anaphylaxis without inducing Fc gammaRIII-mediated
anaphylaxis only when
IgG Ab concentration is high and challenge
allergen dose is low; that
allergen epitope density correlates inversely with the
allergen dose required to induce both
IgE- and Fc gammaRIII-mediated
anaphylaxis; and that both
allergen interception and Fc gammaRIIb-dependent inhibition contribute to in vivo blocking Ab activity.