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

• Published in: Journal of allergy and clinical immunology Vol. 132; no. 6; pp. 1375 - 1387
• Main Authors: Khodoun, Marat V., PhD, Kucuk, Zeynep Yesim, MD, Strait, Richard T., MD, Krishnamurthy, Durga, PhD, Janek, Kevin, BA, Clay, Corey D., MD, PhD, Morris, Suzanne C., PhD, Finkelman, Fred D., MD
• Format: Journal Article
• Language: English
• Published: New York, NY Mosby, Inc 01.12.2013; Elsevier
• Subjects: Allergy and Immunology; Anaphylaxis; Anaphylaxis - immunology; Anaphylaxis - prevention & control; Animals; Antibodies, Blocking - administration & dosage; Antibodies, Blocking - adverse effects; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - adverse effects; basophil; Basophils - drug effects; Basophils - immunology; Biological and medical sciences; Body Temperature - drug effects; Body Temperature - immunology; Desensitization, Immunologic - methods; Disease Models, Animal; FcγR; Female; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Hypersensitivity - complications; Hypersensitivity - therapy; IgG; macrophage; Macrophages - immunology; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; mouse; neutrophil; Neutrophils - drug effects; Neutrophils - immunology; Ovalbumin - immunology; rapid desensitization; Rats; Receptors, IgG - antagonists & inhibitors; Receptors, IgG - immunology; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Platelet-activating factor; HN; HN plus 0.2% NaN3; IgG; rapid desensitization; basophil; Monoclonal antibody; neutrophil; ATCC; mouse; Anaphylaxis; TNP; American Type Culture Collection; Trinitrophenyl; WT; Ovalbumin; macrophage; Egg white; Wild-type; mAb; EW; PAF; HNA; OVA; Hanks balanced salt solution plus 10% newborn bovine serum; FcγR; Allergy; Immunopathology; FcγRII receptor; Immunoglobulins; Rodentia; Granulocyte; Immunoglobulin receptor; Rapid desensitization; FcγR receptor; Basophil; Prevention; FcγIIB receptor; Vertebrata; Mammalia; Immunology; Mouse; Animal; Neutrophil; FcγRIII receptor; Macrophage
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2013.09.008

Background Stimulatory IgG receptors (FcγRs) on bone marrow-derived cells contribute to the pathogenesis of several autoimmune and inflammatory disorders. Monoclonal antibodies that block FcγRs might suppress these diseases, but they can induce anaphylaxis. Objective We wanted to determine whether a rapid desensitization approach can safely suppress IgG/FcγR-mediated anaphylaxis. Methods Mice were injected with serially increasing doses of 2.4G2, a rat mAb that blocks the inhibitory FcγR, FcγRIIb, and the stimulatory receptor, FcγRIII. 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 FcγRI, FcγRIII, and/or FcγRIV 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 FcγRIII and removed most FcγRI and FcγRIV from nucleated peripheral blood cells. Because IgG2a -mediated anaphylaxis was partially FcγRI and FcγRIV dependent, the effects of 2.4G2 on FcγRI and FcγRIV 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 FcγRI, FcγRIII, or FcγRIV on monocycte/macrophages, basophils, or neutrophils and can be safely suppressed by rapid desensitization with anti-FcγRII/RIII mAb. A similar approach may safely suppress other FcγR-dependent immunopathology.