title: Toward a prophylaxis against fetal and neonatal alloimmune thrombocytopenia: induction of antibody-mediated immune suppression and prevention of severe clinical complications in a murine model.
abstract: BACKGROUND
  Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a severe bleeding disorder caused by maternal antibody-mediated destruction of fetal or neonatal platelets (PLTs). Results from our recent large screening study suggest that the pathophysiology of FNAIT is more similar to hemolytic disease of the fetus and newborn (HDFN) than previously thought. Immunization against HPA-1a might therefore be preventable by a prophylactic regimen of inducing antibody-mediated immune suppression (AMIS), which has been documented to be a useful prophylaxis against HDFN. This preclinical proof-of-concept study investigated whether passive administration of anti-β3 integrin could induce AMIS and thereby prevent clinical complications of FNAIT.
  
  
  METHODS
  A murine model of FNAIT using β3 integrin (GPIIIa)-deficient (β3-/-) mice was employed for this study. AMIS in β3-/- mice was induced by intravenous administration of human anti-HPA-1a immunoglobulin G or murine anti-β3 antisera given as prophylaxis after transfusion of HPA-1a-positive human PLTs or murine wild-type PLTs, respectively.
  
  
  RESULTS
  AMIS against both human and murine PLT antigens was induced using this prophylactic approach, reducing the amount of maternal PLT antibodies by up to 90%. Neonatal PLT counts were significantly increased and pregnancy outcome was improved in a dose-dependent manner. The incidence of intracranial hemorrhage, miscarriage, and dead-born pups in mice receiving high-dose prophylaxis was reduced to that of normal controls. We also observed that the severity of thrombocytopenia inversely correlated with birth weight.
  
  
  CONCLUSIONS
  This work conceptually proves that prophylactic administration of PLT antibodies induces AMIS and prevents poor pregnancy outcome in FNAIT.
authors.affiliation: University Hospital of North Norway, Tromsø, Norway.
authors.forename: Heidi
authors.initials: H
authors.lastname: Tiller
authors.forename: Mette Kjaer
authors.initials: MK
authors.lastname: Killie
authors.forename: Pingguo
authors.initials: P
authors.lastname: Chen
authors.forename: Mariana
authors.initials: M
authors.lastname: Eksteen
authors.forename: Anne
authors.initials: A
authors.lastname: Husebekk
authors.forename: Bjorn
authors.initials: B
authors.lastname: Skogen
authors.forename: Jens
authors.initials: J
authors.lastname: Kjeldsen-Kragh
authors.forename: Heyu
authors.initials: H
authors.lastname: Ni
mesh_terms: D000818:Animals; D016824:Antigens, Human Platelet / Q000276:immunology*; D001787:Blood Group Incompatibility / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D005260:Female; D005315:Fetal Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000494:pharmacology*; D007231:Infant, Newborn; D039661:Integrin beta3 / Q000235:genetics / Q000276:immunology*; D007518:Isoantibodies / Q000276:immunology / Q000494:pharmacology*; D008297:Male; D008431:Maternal-Fetal Exchange / Q000276:immunology*; D011247:Pregnancy; D054098:Thrombocytopenia, Neonatal Alloimmune / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*
chemical_list: D016824:Antigens, Human Platelet; D007074:Immunoglobulin G; D039661:Integrin beta3; D007518:Isoantibodies; C083451:human platelet antigen 1b