IgG-blocking antibodies inhibit IgE-mediated anaphylaxis in vivo through both antigen interception and FcγRIIb cross-linking
Richard T. Strait, … , Suzanne C. Morris, Fred D. Finkelman
Richard T. Strait, … , Suzanne C. Morris, Fred D. Finkelman
Published March 1, 2006
Citation Information: J Clin Invest. 2006;116(3):833-841. https://doi.org/10.1172/JCI25575.
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Research Article Immunology

IgG-blocking antibodies inhibit IgE-mediated anaphylaxis in vivo through both antigen interception and FcγRIIb cross-linking

Abstract

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.

Authors

Richard T. Strait, Suzanne C. Morris, Fred D. Finkelman

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Identification of the serum factor that blocks IgE-mediated anaphylaxis ...
Identification of the serum factor that blocks IgE-mediated anaphylaxis as Ag-specific IgG. (A) BALB/c mice (5 per group) were primed with 10 μg of IgEαTNP i.v., then challenged i.v. 24 hours later with the doses of TNP-OVA shown on the abscissa. Maximum temperature decreases during the 90 minutes after challenge were calculated for this and all subsequent panels. (B) BALB/c mice (5 per group) were primed i.v. with the doses of αTNP Asm shown on the abscissa and challenged i.v. 24 hours later with the indicated doses of TNP-OVA. (C) BALB/c mice (5 per group) were primed i.v. with 10 μg of IgEαTNP, 250 μl of αGIgG Asm, and/or 250 μl of αTNP Asm as indicated, and challenged i.v. 24 hours later with 1 μg of TNP-OVA. *P < 0.05. (D) BALB/c mice (5 per group) were primed i.v. with 10 μg of IgEαTNP plus saline, 250 μl of IgGαTNP, or 125 μl of αTNP Asm, then challenged i.v. 24 hours later with 70 ng of TNP-OVA. (E) BALB/c mice (5 per group) were primed i.v. with 250 μl of IgGαTNP, then challenged i.v. 24 hours later with 70 ng or 500 μg of TNP-OVA. (F) BALB/c mice (5 per group) were primed i.v. with either 10 μg of IgEαTNP or 250 μl of αTNP Asm or both and treated with saline or 500 μg of anti–FcγRII/RIII mAb. Mice were challenged i.v. 24 hours later with 1 or 500 μg of TNP-OVA.