title: Prevention of Defective Placentation and Pregnancy Loss by Blocking Innate Immune Pathways in a Syngeneic Model of Placental Insufficiency.
abstract: Defective placentation and subsequent placental insufficiency lead to maternal and fetal adverse pregnancy outcome, but their pathologic mechanisms are unclear, and treatment remains elusive. The mildly hypertensive BPH/5 mouse recapitulates many features of human adverse pregnancy outcome, with pregnancies characterized by fetal loss, growth restriction, abnormal placental development, and defects in maternal decidual arteries. Using this model, we show that recruitment of neutrophils triggered by complement activation at the maternal/fetal interface leads to elevation in local TNF-α levels, reduction of the essential angiogenic factor vascular endothelial growth factor, and, ultimately, abnormal placentation and fetal death. Blockade of complement with inhibitors specifically targeted to sites of complement activation, depletion of neutrophils, or blockade of TNF-α improves spiral artery remodeling and rescues pregnancies. These data underscore the importance of innate immune system activation in the pathogenesis of placental insufficiency and identify novel methods for treatment of pregnancy loss mediated by abnormal placentation.
authors.affiliation: Department of Obstetrics and Gynecology, Weill Cornell Medical Center, New York, NY 10065;
authors.forename: Shari E
authors.initials: SE
authors.lastname: Gelber
authors.affiliation: Department of Obstetrics and Gynecology, Weill Cornell Medical Center, New York, NY 10065;
authors.forename: Elyssa
authors.initials: E
authors.lastname: Brent
authors.affiliation: Department of Medicine, Hospital for Special Surgery, Weill Cornell Medical Center, New York, NY 10021;
authors.forename: Patricia
authors.initials: P
authors.lastname: Redecha
authors.affiliation: Department of Pathology and Laboratory Medicine, Hospital for Special Surgery, New York, NY 10021;
authors.forename: Giorgio
authors.initials: G
authors.lastname: Perino
authors.affiliation: Department of Microbiology and Immunology, Darby Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425; Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 29401;
authors.forename: Stephen
authors.initials: S
authors.lastname: Tomlinson
authors.affiliation: Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853; and Department of Cell and Developmental Biology, Weill Cornell Medical Center, New York, NY 10065.
authors.forename: Robin L
authors.initials: RL
authors.lastname: Davisson
authors.affiliation: Department of Medicine, Hospital for Special Surgery, Weill Cornell Medical Center, New York, NY 10021; SalmonJ@hss.edu.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Salmon
mesh_terms: D000022:Abortion, Spontaneous / Q000276:immunology / Q000517:prevention & control*; D000818:Animals; D002460:Cell Line; D003167:Complement Activation / Q000276:immunology*; D003169:Complement Inactivator Proteins / Q000494:pharmacology; D003165:Complement System Proteins / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D005313:Fetal Death; D005317:Fetal Growth Retardation / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration / Q000276:immunology; D009504:Neutrophils / Q000276:immunology*; D010920:Placenta / Q000166:cytology; D010927:Placental Insufficiency / Q000276:immunology / Q000517:prevention & control*; D010929:Placentation / Q000276:immunology*; D011247:Pregnancy; D014327:Trophoblasts / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D003169:Complement Inactivator Proteins; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D003165:Complement System Proteins