Rapid desensitization of humanized mice with anti-human Fc?RI? monoclonal antibodies.

ABSTRACT: BACKGROUND:Anaphylaxis is classically mediated by allergen cross-linking of IgE bound to the ? chain of Fc?RI, the mast cell/basophil high affinity IgE receptor. Allergen cross-linking of the IgE/Fc?RI complex activates these cells, inducing release of disease-causing mediators, cytokines, and enzymes. We previously demonstrated that IgE-mediated anaphylaxis could be safely prevented in wild-type BALB/c mice by rapid desensitization with anti-mouse Fc?RI? mAb. OBJECTIVE:This study sought to use humanized mice to extend these results to humans. METHODS:We actively immunized huFc?RI?/F709 mice, which express human (hu) instead of mouse Fc?RI? and a mutant IL-4 receptor that lacks inhibitory function. We passively immunized huFc?RI? mice, as well as human cord blood-reconstituted reNSGS mice, which are immune-deficient, produce mast cell-stimulating human cytokines, and develop numerous human mast cells. For desensitization, we used anti-huFc?RI? mAbs that bind Fc?RI? regardless of its association with IgE (noncompeting mAbs), and/or mAbs that compete with IgE for huFc?RI? binding (competing mAbs). Anaphylaxis was induced by intravenous injection of antigen or anti-huIgE mAb. RESULTS:Anti-huFc?RI? mAb rapid desensitization was safer and more effective than allergen rapid desensitization and suppressed anaphylaxis more rapidly than omalizumab or ligelizumab. Rapid desensitization of naïve, IgE-sensitized huFc?RI? mice and huFc?RI?/F709 mice that were egg-allergic with anti-Fc?RI? mAbs safely removed >98% of IgE from peritoneal mast cells and completely suppressed IgE-mediated anaphylaxis. Rapid desensitization of reNSGS mice with anti-Fc?RI? mAbs also safely removed ?98% of mast cell IgE and prevented IgE-mediated anaphylaxis. CONCLUSIONS:Rapid desensitization with anti-Fc?RI? mAbs may be a safe, effective, and practical way to prevent IgE-mediated anaphylaxis.

SUBMITTER: Khodoun MV 

PROVIDER: S-EPMC7607676 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature