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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Figure 1

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FcγRIII-independent anaphylaxis in GαMD-primed mice requires challenge w...
FcγRIII-independent anaphylaxis in GαMD-primed mice requires challenge with a high dose of Ag. (A) BALB/c mice (5 per group) were primed s.c. with GαMD, then challenged i.v. 14 days later with 0.1 or 10 mg of GIgG. Some mice were pretreated 24 hours before GIgG challenge with 500 μg of anti–FcγRII/RIII mAb to block IgG-mediated anaphylaxis. Rectal temperatures were followed for 2 hours after challenge. (B) Mice primed and challenged as in A had blood drawn before and 15 minutes after challenge. Hematocrit levels were determined. *P < 0.05 compared with mice treated with anti–FcγRII/RIII mAb and challenged with 0.1 mg of GIgG. (C) WT (left) and FcγRIII-deficient mice (right) were primed s.c. with GαMD, then challenged i.v. 14 days later with 10 mg of GIgG. Some mice were injected s.c. with 500 μg of anti–FcγRII/RIII mAb 24 hours before GIgG challenge. Rectal temperatures were followed for 90 minutes after challenge. (D) BALB/c mice were primed s.c. with TNP-GαMD or saline, then challenged 14 days later with 0, 0.01, or 1 mg of biotinylated TNP-OVA. Blood was drawn 5 minutes later, and IgG1–TNP-OVA complexes in serum were quantitated by ELISA. *P < 0.05 compared with other measured levels. (E) TNP-OVA-NIP was diluted in nonimmune serum or heat-inactivated serum pooled from mice immunized 10–12 days earlier with GαMD (αGIgG Asm) or TNP-GαMD (αTNP Asm). Binding of serum TNP-OVA-NIP by IgEαTNP was measured by ELISA. Means ± SEMs are shown for all data in this and subsequent figures unless otherwise indicated.