Anti-FcγRIIB mAb suppresses murine IgG-dependent anaphylaxis by Fc domain targeting of FcγRIII

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Background:The inhibitory receptor FcγRIIB is expressed on human and murine bone marrow–derived cells and limits inflammation by suppressing signaling through stimulatory receptors.Objective:We sought to evaluate the effects of K9.361, a mouse IgG2a alloantibody to mouse FcγRIIB, on murine anaphylaxis.Methods:Wild-type and FcγR-deficient mice were used to study anaphylaxis, which was induced by injection of 2.4G2 (rat IgG2b mAb that binds both FcγRIIB and the stimulatory receptor FcγRIII), by actively immunizing IgE-deficient mice and then challenging with the immunizing antigen, and by passive immunization with IgG or IgE anti–2,4,6-trinitrophenyl mAb, followed by injection of 2,4,6-trinitrophenyl–ovalbumin. Pretreatment with K9.361 was assessed for its ability to influence anaphylaxis.Results:Unexpectedly, K9.361 injection induced mild anaphylaxis, which was both FcγRIIB and FcγRIII dependent and greatly enhanced by β-adrenergic blockade. K9.361 injection also decreased expression of stimulatory Fcγ receptors, especially FcγRIII, and strongly suppressed IgG-mediated anaphylaxis without strongly affecting IgE-mediated anaphylaxis. The F(ab′)2 fragment of K9.361 did not induce anaphylaxis, even after β-adrenergic blockade, and did not deplete FcγRIII or suppress IgG-mediated anaphylaxis but prevented intact K9.361-induced anaphylaxis without diminishing intact K9.36 suppression of IgG-mediated anaphylaxis.Conclusion:Cross-linking FcγRIIB to stimulatory FcγRs through the Fc domains of an anti-FcγRIIB mAb induces and then suppresses IgG-mediated anaphylaxis without affecting IgE-mediated anaphylaxis. Because IgG- and IgE-mediated anaphylaxis can be mediated by the same cell types, this suggests that desensitization acts at the receptor rather than cellular level. Sequential treatment with the F(ab′)2 fragment of anti-FcγRIIB mAb followed by intact anti-FcγRIIB safely prevents IgG-mediated anaphylaxis.

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