Anti-Fc gamma RIIB mAb suppresses murine IgG-dependent anaphylaxis by Fc domain targeting of Fc gamma RIII

作者：Clay Corey D; Strait Richard T; Mahler Ashley; Khodoun Marat V; Finkelman Fred D^*

来源：Journal of Allergy and Clinical Immunology, 2018, 141(4): 1373-+.

DOI：10.1016/j.jaci.2017.05.027

• Fc receptors
• anaphylaxis
• mouse
• signaling
• IgG
• IgE

Background: The inhibitory receptor Fc gamma RIIB 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 IgG(2a) alloantibody to mouse Fc gamma RIIB, on murine anaphylaxis.
Methods: Wild-type and Fc gamma R-deficient mice were used to study anaphylaxis, which was induced by injection of 2.4G2 (rat IgG(2b) mAb that binds both Fc gamma RIIB and the stimulatory receptor Fc gamma RIII), 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 Fc gamma RIIB and Fc gamma RIII dependent and greatly enhanced by beta-adrenergic blockade. K9.361 injection also decreased expression of stimulatory Fc gamma receptors, especially Fc gamma RIII, 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 b-adrenergic blockade, and did not deplete Fc gamma RIII 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 Fc gamma RIIB to stimulatory Fc gamma Rs through the Fc domains of an anti-Fc gamma RIIB 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-Fc gamma RIIB mAb followed by intact anti-Fc gamma RIIB safely prevents IgG-mediated anaphylaxis.

• 出版日期2018-4