First infusion reactions are mediated by FcγRIIIb and neutrophils
Weber F, Breustedt D, Schlicht S, Meyer CA, Niewoehner J, Ebeling M, Freskgard PO, Bruenker P, Singer T, Reth M, Iglesias A
Administration of therapeutic monoclonal antibodies (mAbs) is frequently accompanied by severe first infusion reactions (FIR). The mechanism driving FIR is still unclear. This study investigates the cellular and molecular mechanisms causing FIR in humanized mouse models and their potential for evaluating FIR risk in patients. Infusion of human mAb specific for mouse transferrin receptor (HamTfR) into FcgammaR-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 FcgammaRIIIb on neutrophils was both necessary and sufficient to cause FIR. In summary we found that human FcgammaRIIIb and neutrophils are primarily responsible for triggering FIR. Thus clinical strategies to prevent FIR in patients should focus on this pathway and may include transient depletion of neutrophils or blocking FcgammaRIIIb with specific mAbs.
