title: Anti-phospholipid induced murine fetal loss: novel protective effect of a peptide targeting the β2 glycoprotein I phospholipid-binding site. Implications for human fetal loss.
abstract: β2 glycoprotein I (β2GPI)-dependent anti-phospholipid antibodies (aPL) induce thrombosis and affect pregnancy. The CMV-derived synthetic peptide TIFI mimics the PL-binding site of β2GPI and inhibits β2GPI cell-binding in vitro and aPL-mediated thrombosis in vivo. Here we investigated the effect of TIFI on aPL-induced fetal loss in mice. TIFI inhibitory effect on in vitro aPL binding to human trophoblasts was evaluated by indirect immunofluorescence and ELISA. TIFI effect on aPL-induced fetal loss was investigated in pregnant C57BL/6 mice treated with aPL or normal IgG (NHS). Placenta/fetus weight and histology and RNA expression were analyzed. TIFI, but not the control peptide VITT, displayed a dose-dependent inhibition of aPL binding to trophoblasts in vitro. Injection of low doses of aPL at day 0 of pregnancy caused growth retardation and increased fetal loss rate, both significantly reduced by TIFI but not VITT. Consistent with observations in humans, histological analysis showed no evidence of inflammation in this model, as confirmed by the absence of an inflammatory signature in gene expression analysis, which in turn revealed a TIFI-dependent modulation of molecules involved in differentiation and development processes. These findings support the non-inflammatory pathogenic role of aPL and suggest innovative therapeutic approaches to aPL-dependent fetal loss.
authors.affiliation: Istituto Clinico Humanitas, Rozzano, Italy.
authors.forename: Yeny Martinez
authors.initials: YM
authors.lastname: de la Torre
authors.forename: Francesca
authors.initials: F
authors.lastname: Pregnolato
authors.forename: Fabio
authors.initials: F
authors.lastname: D'Amelio
authors.forename: Claudia
authors.initials: C
authors.lastname: Grossi
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Di Simone
authors.forename: Fabio
authors.initials: F
authors.lastname: Pasqualini
authors.forename: Manuela
authors.initials: M
authors.lastname: Nebuloni
authors.forename: Pojen
authors.initials: P
authors.lastname: Chen
authors.forename: Silvia
authors.initials: S
authors.lastname: Pierangeli
authors.forename: Niccolò
authors.initials: N
authors.lastname: Bassani
authors.forename: Federico
authors.initials: F
authors.lastname: Ambrogi
authors.forename: Maria-Orietta
authors.initials: MO
authors.lastname: Borghi
authors.forename: Annunciata
authors.initials: A
authors.lastname: Vecchi
authors.forename: Massimo
authors.initials: M
authors.lastname: Locati
authors.forename: Pier-Luigi
authors.initials: PL
authors.lastname: Meroni
mesh_terms: D000022:Abortion, Spontaneous / Q000276:immunology* / Q000517:prevention & control; D000818:Animals; D017152:Antibodies, Antiphospholipid / Q000276:immunology* / Q000378:metabolism; D001665:Binding Sites; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D010920:Placenta / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D011485:Protein Binding; D014327:Trophoblasts / Q000187:drug effects / Q000378:metabolism; D053482:beta 2-Glycoprotein I / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D017152:Antibodies, Antiphospholipid; D010455:Peptides; C516775:TIFI peptide; D053482:beta 2-Glycoprotein I