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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 FcεRI-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 FcγRIII 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 FcεRI to the inhibitory IgG receptor FcγRIIb. 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 FcγRIII-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 FcγRIII-mediated anaphylaxis; and that both allergen interception and FcγRIIb-dependent inhibition contribute to in vivo blocking Ab activity.
Nonstandard abbreviations used: Ag, antigen; Asm, antiserum; BA, blocking antibody; GIgG, goat IgG; αGIgG Asm, heat-inactivated mouse anti-GIgG antiserum; GoMD, goat anti-mouse IgD antiserum; IgEαTNP, IgE anti-TNP mAb; IgGαGIgG, IgG anti-GIgG; IgGαTNP, purified IgG fraction of αTNP Asm; IVCCA, in vivo cytokine capture assay; MMCP-1, mouse mast cell protease-1; NIP, 3-nitro-4-hydroxy-5-iodophenylacetyl; PAF, platelet-activating factor; TNP, trinitrophenyl; αTNP Asm, heat-inactivated mouse anti-TNP anriserum; TNP-GαMD, TNP conjugated to GaMD; TNP-OVA, TNP conjugated to OVA; TNP-OVA-NIP, NIP conjugated to TNP-OVA.
Conflict of interest: The authors have declared that no conflict of interest exists.
Citation for this arade: J. Clin. Invest. 116:833-841 (2006). doi:10.1172/JCI25575.
Introduction
The rationale for allergen immunotherapy for atopic disorders has changed with time. Initially, "allergy vaccines" were thought to induce the production of IgG blocking antibody (BA), which might neutralize allergen molecules before they could interact with what were later discovered to be IgE Abs bound to FcεRI on mast cells and basophils (1,2). More recently, this BA concept has been supplemented by evidence that IgG Ab-allergen complexes may inhibit mast cell signaling by...