First Infusion Reactions are Mediated by FcγRIIIb and Neutrophils
| Autor: | Felix C. Weber, Claas A. Meyer, Martin Ebeling, Per-Ola Freskgard, Antonio Iglesias, Michael Reth, Peter Bruenker, Thomas Singer, Sonja Schlicht, Daniel Breustedt, Jens Niewoehner |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
humanized mouse model medicine.drug_class Neutrophils medicine.medical_treatment Pharmaceutical Science Transferrin receptor Inflammation Mice Transgenic Hypothermia Monoclonal antibody GPI-Linked Proteins Proinflammatory cytokine 03 medical and health sciences Mice Receptors Transferrin medicine Animals Humans Pharmacology (medical) Receptor Pharmacology infusion reactions human FcγRIIIb biology Chemistry Organic Chemistry Receptors IgG Antibodies Monoclonal Mice Inbred C57BL immunotoxicology 030104 developmental biology Cytokine Integrin alpha M Humanized mouse Immunology biology.protein Molecular Medicine medicine.symptom Biotechnology Research Paper |
| Zdroj: | Pharmaceutical Research |
| ISSN: | 1573-904X |
| Popis: | Purpose Administration of therapeutic monoclonal antibodies (mAbs) is frequently accompanied by severe first infusion reactions (FIR). The mechanism driving FIR is still unclear. This study aimed to investigate the cellular and molecular mechanisms causing FIR in humanized mouse models and their potential for evaluating FIR risk in patients. Methods Mice humanized for Fc gamma receptors (FcγRs) were generated by recombination-mediated genomic replacement. Body temperature, cytokine release and reactive oxygen species (ROS) were measured to assess FIR to mAbs. Results Infusion of human mAb specific for mouse transferrin receptor (HamTfR) into FcγR-humanized mice, produced marked transient hypothermia accompanied by an increase in inflammatory cytokines KC and MIP-2, and ROS. FIR were dependent on administration route and Fc-triggered effector functions mediated by neutrophils. Human neutrophils also induced FIR in wild type mice infused with HamTfR. Specific knock-in mice demonstrated that human FcγRIIIb on neutrophils was both necessary and sufficient to cause FIR. FcγRIIIb-mediated FIR was abolished by depleting neutrophils or blocking FcγRIIIb with CD11b antibodies. Conclusions Human FcγRIIIb and neutrophils are primarily responsible for triggering FIR. Clinical strategies to prevent FIR in patients should focus on this pathway and may include transient depletion of neutrophils or blocking FcγRIIIb with specific mAbs. Electronic supplementary material The online version of this article (10.1007/s11095-018-2448-8) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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