A novel murine model of fetal and neonatal alloimmune thrombocytopenia: response to intravenous IgG therapy

Author:

Ni Heyu1,Chen Pingguo1,Spring Christopher M.1,Sayeh Ebrahim1,Semple John W.1,Lazarus Alan H.1,Hynes Richard O.1,Freedman John1

Affiliation:

1. From the Departments of Laboratory Medicine and Pathobiology, Medicine, and Pharmacology, University of Toronto, ON, Canada; The Canadian Blood Services, Ottawa, ON, Canada; The Toronto Platelet Immunobiology Group, St Michael's Hospital, Toronto, ON, Canada; and the Department of Biology, Howard Hughes Medical Institute and Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, MA.

Abstract

AbstractFetal and neonatal alloimmune thrombo cytopenia (FNAITP) is a life-threatening bleeding disorder caused by maternal antibodies directed against fetal platelet antigens. The immunoreactive epitopes in FNAITP are primarily located in the extracellular regions of the platelet glycoprotein IIIa (β3 integrin). Here we have established a novel animal model of FNAITP using β3 integrin–deficient (β3-/-) mice. We demonstrated first that these mice are immunoresponsive to β3 integrin; β3-/- mice transfused with wild-type platelets generated specific anti–β3 antibodies which were able to induce thrombocytopenia in wild-type mice. Subsequently, β3-/- female mice (both naive and immunized) were bred with wild-type male mice to recapitulate the features of FNAITP. The titer of generated maternal antibodies correlated with the severity of FNAITP. High titer maternal anti–β3 anti-bodies caused severe fetal thrombocytopenia, intracranial hemorrhage, and even miscarriage. Furthermore, maternal administration of intravenous immunoglobulin G (IgG) ameliorated FNAITP and down-regulated pathogenic antibodies in both the maternal and fetal circulations.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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