Identification of critical antigen-specific mechanisms in the development of immune thrombocytopenic purpura in mice.
The pathogenic effects of antiplatelet antibodies were investigated in mice. Monoclonal antibodies (mAbs) of different immunoglobulin G subclass directed against mouse GPIIbIIIa, GPIIIa, GPIbalpha, GPIb-IX, GPV, and CD31 were generated and characterized biochemically. MAbs against GPIb-IX, GPV, CD31, and linear epitopes on GPIIIa had mild and transient effects on platelet counts and induced no spontaneous bleeding. Anti-GPIbalpha mAbs induced profound irreversible thrombocytopenia (< 3% of normal) by Fc-independent mechanisms but only had minor effects on hematocrits. In contrast, injection of intact mAbs, but not F(ab)(2) fragments, against conformational epitopes on GPIIbIIIa, induced irreversible thrombocytopenia, acute systemic reactions, hypothermia, decreased hematocrits, and a paradoxical loss of surface GPIIbIIIa on platelets in vivo, the latter suggesting the formation of platelet-derived microparticles. Blockage of platelet-activating factor receptors inhibited the acute reactions, but not thrombocytopenia, loss of GPIIbIIIa, and decreases in hematocrits. Repeated injections of low doses of anti-GPIIbIIIa antibodies resulted in profound thrombocytopenia and bleeding, whereas no acute systemic reactions were observed. These data strongly suggest that the identity of the target antigen recognized by antiplatelet antibodies determines the mechanisms of platelet destruction and the severity of bleeding in mice, the latter depending on previously unrecognized anti-GPIIbIIIa-specific inflammatory mechanisms.
Nieswandt
B
B
Department of Molecular Oncology, General Surgery, University of Witten-Herdecke, Wuppertal, Germany. nieswand@klinikum-wuppertal.de
Bergmeier
W
W
Rackebrandt
K
K
Gessner
J E
JE
Zirngibl
H
H
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology; D001324:Autoantigens / Q000276:immunology*; D001792:Blood Platelets / Q000737:chemistry / Q000276:immunology*; D000939:Epitopes; D006470:Hemorrhage / Q000276:immunology; D007141:Immunoglobulin Fc Fragments / Q000276:immunology / Q000494:pharmacology; D007074:Immunoglobulin G / Q000494:pharmacology; D051379:Mice; D010641:Phenotype; D010972:Platelet Activating Factor / Q000494:pharmacology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000276:immunology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000276:immunology; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000276:immunology; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000276:immunology*; D013047:Specific Pathogen-Free Organisms
D000911:Antibodies, Monoclonal; D001324:Autoantigens; D000939:Epitopes; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D010972:Platelet Activating Factor; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D019038:Platelet Glycoprotein GPIb-IX Complex