Humanized mouse models of FcR clearance in immune platelet disorders.
Transgenic mouse lines expressing physiologic levels of human platelet Fc receptor (FcR) for IgG, Fc gamma RIIA, on platelets and macrophages were generated. Anti-CD9 antibody activated platelets of Fc gamma RIIA transgenic mice and, following injection in vivo, caused rapid and severe thrombocytopenia compared with nonactivating antiplatelet antibody. Anti-CD9 injected in Fc gamma RIIA transgenic mice crossed with FcR gamma-chain knockout (gamma-KO) mice caused thrombosis and shock in all mice, and death in 16 of 18 mice. Histologic examination of lung vasculature of anti-CD-treated Fc gamma RIIA transgenic x gamma-KO mice showed extensive platelet-fibrin thrombi. Taken together, these observations suggest that in Fc gamma RIIA transgenic x gamma-KO mice there is an important interplay of intravascular platelet activation and splenic clearance. Reduction of splenic clearance surgically or functionally also facilitated anti-CD-9-mediated shock in Fc gamma RIIA transgenic mice. Thus, antibodies that activate platelets in an Fc gamma RIIA-dependent manner lead to thrombosis, shock, and death. These mouse model findings have implications for human immune-mediated thrombocytopenic disorders. Genetic factors may be important in the interindividual variability seen clinically, and with nonactivating platelet antibody the spleen is largely responsible for the thrombocytopenia. This is likely the case in typical idiopathic thrombocytopenic purpura (ITP). For several other immune thrombocytopenic disorders, the spleen probably plays a second, protective role in removing antibody-coated platelets from the circulation.
McKenzie
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Cardeza Foundation for Hematologic Research, Thomas Jefferson University, Philadelphia, PA 19107, USA. steven.mckenzie@mail.tju.edu
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism / Q000502:physiology; D001791:Blood Platelet Disorders / Q000209:etiology / Q000276:immunology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic / Q000097:blood* / Q000276:immunology; D011961:Receptors, Fc / Q000378:metabolism / Q000502:physiology; D017452:Receptors, IgG / Q000378:metabolism / Q000502:physiology; D013921:Thrombocytopenia / Q000209:etiology / Q000276:immunology; D013927:Thrombosis / Q000209:etiology / Q000276:immunology
D015703:Antigens, CD; C080568:Fc gamma receptor IIA; D011961:Receptors, Fc; D017452:Receptors, IgG