Acute systemic reaction and lung alterations induced by an antiplatelet integrin gpIIb/IIIa antibody in mice.
Shock is frequently accompanied by thrombocytopenia. To investigate the pathogenic role of platelets in shock, we examined the in vivo effects of monoclonal antibodies (MoAbs) against mouse platelet membrane proteins. Injection of the platelet-specific MoAb MWReg30 to the fibrinogen receptor (gpIIb/IIIa) rendered mice severely hypothermic within minutes. Isotype-matched control antibodies, even if they also recognized platelet surface antigens, did not induce comparable signs. MWReg30 induced early signs of acute lung injury with increased cellularity in the lung interstitium and rapid engorgement of alveolar septal vessels. Despite this in vivo activity, MWReg30 inhibited rather than stimulated platelet aggregation in vitro. MWReg30-binding to platelets led to phosphorylation of gpIIIa, but did not induce morphological signs of platelet activation. The MWReg30-induced reaction was abolished after treatment with MoAbs 2.4G2 to FcgammaRII/III and was absent in FcgammaRIII-deficient mice, clearly demonstrating the requirement for FcgammaRIII on involved leukocytes. Simultaneous administration of tumor necrosis factor exacerbated, whereas a tolerizing regimen of tumor necrosis factor or bacterial lipopolysaccharide completely prevented the reaction. These data suggest that platelet surface-deposited MWReg30-immune complexes lead to an acute Fc-mediated reaction with pulmonary congestion and life-threatening potential that could serve as an in vivo model of acute lung injury.
Department of Pathology, Tumor Immunology, University of Regensburg, Regensburg, Germany.
B
B
Nieswandt
B
B
Echtenacher
F P
FP
Wachs
J
J
Schröder
J E
JE
Gessner
R E
RE
Schmidt
G E
GE
Grau
D N
DN
Männel
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000633:toxicity*; D000936:Antigen-Antibody Complex / Q000276:immunology; D004890:Erythema / Q000209:etiology / Q000276:immunology / Q000503:physiopathology; D007035:Hypothermia / Q000209:etiology / Q000276:immunology / Q000503:physiopathology; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000627:therapeutic use; D008168:Lung / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D010766:Phosphorylation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000276:immunology* / Q000502:physiology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011654:Pulmonary Edema / Q000209:etiology* / Q000276:immunology / Q000503:physiopathology; D017452:Receptors, IgG / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D012769:Shock / Q000150:complications / Q000209:etiology* / Q000503:physiopathology / Q000517:prevention & control; D013047:Specific Pathogen-Free Organisms; D013921:Thrombocytopenia / Q000209:etiology* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity
D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; D008070:Lipopolysaccharides; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D017452:Receptors, IgG; D014409:Tumor Necrosis Factor-alpha