Rapid desensitization of mice with anti-FcγRIIb/FcγRIII mAb safely prevents IgG-mediated anaphylaxis

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:132

Article

Khodoun, Marat V.^1,2  Kucuk, Zeynep Yesim³  Strait, Richard T.^1,4  Krishnamurthy, Durga^1,2  Janek, Kevin⁵  Clay, Corey D.²  Morris, Suzanne C.^1,2  Finkelman, Fred D.^2,6,7 

[1] Cincinnati Vet Affairs Med Ctr, Dept Res, Cincinnati, OH USA

[2] Univ Cincinnati, Sch Med, Div Immunol Allergy & Rheumatol, Dept Med, Cincinnati, OH 45267 USA

[3] Cincinnati Childrens Hosp Med Ctr, Div Allergy & Immunol, Cincinnati, OH 45229 USA

[4] Cincinnati Childrens Hosp Med Ctr, Div Emergency Med, Cincinnati, OH 45229 USA

[5] Univ Cincinnati, Sch Med, Cincinnati, OH 45267 USA

[6] Cincinnati Vet Affairs Med Ctr, Dept Med, Cincinnati, OH USA

[7] Cincinnati Childrens Hosp Med Ctr, Div Cellular & Mol Immunol, Cincinnati, OH 45229 USA

关键词: Anaphylaxis;    IgG;    Fc gamma R;    mouse;    macrophage;    basophil;    neutrophil;    rapid desensitization;   

DOI  :  10.1016/j.jaci.2013.09.008

来源: Elsevier

【 摘 要 】

Background: Stimulatory IgG receptors (Fc gamma Rs) on bone marrow-derived cells contribute to the pathogenesis of several autoimmune and inflammatory disorders. Monoclonal antibodies that block Fc gamma Rs might suppress these diseases, but they can induce anaphylaxis. Objective: We wanted to determine whether a rapid desensitization approach can safely suppress IgG/Fc gamma R-mediated anaphylaxis. Methods: Mice were injected with serially increasing doses of 2.4G2, a rat mAb that blocks the inhibitory Fc gamma R, Fc gamma RIIb, and the stimulatory receptor, Fc gamma RIII. Rectal temperature was used to detect the development of anaphylaxis. Passive and active IgG-mediated anaphylaxis were evaluated in mice that had been rapidly desensitized with 2.4G2 or mock-desensitized in mice in which monocyte/macrophages, basophils, or neutrophils had been depleted or desensitized and in mice in which Fc gamma RI, Fc gamma RIII, and/or FcgRIV had been deleted or blocked. Results: Rapid desensitization with 2.4G2 prevented 2.4G2-induced shock and completely suppressed IgG-mediated anaphylaxis. Rapid desensitization of ovalbumin-sensitized mice with 2.4G2 was safer and more effective than rapid desensitization with ovalbumin. 2.4G2 treatment completely blocked FcgRIII and removed most Fc gamma RI and Fc gamma RIV from nucleated peripheral blood cells. Because IgG2a-mediated anaphylaxis was partially FcgRI and FcgRIV dependent, the effects of 2.4G2 on Fc gamma RI and Fc gamma RIV were probably crucial for its complete inhibition of IgG2a-mediated anaphylaxis. IgG2a-mediated anaphylaxis was partially inhibited by depletion or desensitization of monocyte/macrophages, basophils, or neutrophils. Conclusion: IgG-mediated anaphylaxis can be induced by ligation of Fc gamma RI, Fc gamma RIII, or Fc gamma RIV on monocycte/macrophages, basophils, or neutrophils and can be safely suppressed by rapid desensitization with anti-Fc gamma RII/RIII mAb. A similar approach may safely suppress other Fc gamma R-dependent immunopathology.

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