title: Rapid desensitization of mice with anti-FcγRIIb/FcγRIII mAb safely prevents IgG-mediated anaphylaxis.
abstract: 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 IgG(2a)-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 IgG(2a)-mediated anaphylaxis. IgG(2a)-mediated anaphylaxis was partially inhibited by depletion or desensitization of monocyte/macrophages, basophils, or neutrophils.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Research, Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio; Division of Immunology, Allergy and Rheumatology, Department of Medicine, University of Cincinnati School of Medicine, Cincinnati, Ohio.
authors.forename: Marat V
authors.initials: MV
authors.lastname: Khodoun
authors.forename: Zeynep Yesim
authors.initials: ZY
authors.lastname: Kucuk
authors.forename: Richard T
authors.initials: RT
authors.lastname: Strait
authors.forename: Durga
authors.initials: D
authors.lastname: Krishnamurthy
authors.forename: Kevin
authors.initials: K
authors.lastname: Janek
authors.forename: Corey D
authors.initials: CD
authors.lastname: Clay
authors.forename: Suzanne C
authors.initials: SC
authors.lastname: Morris
authors.forename: Fred D
authors.initials: FD
authors.lastname: Finkelman
mesh_terms: D000707:Anaphylaxis / Q000276:immunology / Q000517:prevention & control*; D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage* / Q000009:adverse effects; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D001491:Basophils / Q000187:drug effects / Q000276:immunology; D001831:Body Temperature / Q000187:drug effects / Q000276:immunology; D003888:Desensitization, Immunologic / Q000379:methods*; D004195:Disease Models, Animal; D005260:Female; D006967:Hypersensitivity / Q000150:complications / Q000628:therapy*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D010047:Ovalbumin / Q000276:immunology; D051381:Rats; D017452:Receptors, IgG / Q000037:antagonists & inhibitors* / Q000276:immunology
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; C499172:Fcgr2b protein, mouse; C485700:Fcgr3 protein, mouse; D017452:Receptors, IgG; D010047:Ovalbumin
keywords: ATCC; American Type Culture Collection; Anaphylaxis; EW; Egg white; FcγR; HN; HN plus 0.2% NaN3; HNA; Hanks balanced salt solution plus 10% newborn bovine serum; IgG; Monoclonal antibody; OVA; Ovalbumin; PAF; Platelet-activating factor; TNP; Trinitrophenyl; WT; Wild-type; basophil; mAb; macrophage; mouse; neutrophil; rapid desensitization