Purpose: b2GPI-dependent aPL can cause recurrent pregnancy loss & pregnancy complications by triggering placental thrombosis & by reacting with b2GPI expressed on trophoblast & decidual cells. aPL mediate a local inflammatory process & functional trophoblast/decidual cell abnormalities leading to a defective placentation. A 20 aa CMV derived synthetic peptide (TIFI) sharing similarity with the putative PL-binding site in the Vth domain of b2GPI reverses aPL-mediated thrombosis in vivo & inhibits in vitro binding of FITC b2GPI to human endothelium & murine monocytes. Aim of the study was to investigate the ability of TIFI to protect pregnant naïve mice from aPL-induced foetal loss. Methods: In vivo studies. Pregnant C57BL/6 mice were injected with IgG from APS patients (aPL-IgG) or with normal human IgG (NHS-IgG) (50 μg iv the day after mating - day 0). Treated animals were divided into: group A which received 40 ug of TIFI/mouse i.p. 30 min before the infusion of IgG at day 0, & at day 5 & 10 of pregnancy; group B which received 40 ug of a control peptide (VITT) & group C which received saline at the same times. 20 animals/group were studied. The animals were sacrificed at day 15 of pregnancy & the placentas/foetuses collected & analyzed for weight & histology as described (Martinez de la Torre et al PNAS 2007;104:2319-24). In vitro studies: binding of aPL-IgG & human b2GPI-dependent aPL IgG mAb (IS3) to human trophoblast & decidual cell monolayers was investigated as described (Di Simone et al Arthritis Rheum 2000;43:140-51); aPL binding was evaluated in the presence or in the absence of serial concentrations of TIFI or VITT (5-20 ug/ml). Results: aPL-IgG treated animals displayed: higher number of foetal losses & reduced placental/foetal weights vs animals treated with NHS-IgG (p< 0.01). Control peptide (VITT) treatment did not display any effect, while the number of animals with foetal loss & histological lesions at the foetal placental side were significantly reduced after TIFI injection (p<0.01).TIFI, but not VITT, displayed a dose-dependent inhibitory effect on both polyclonal aPL IgG fraction & IS3 mAb binding to trophoblast & decidual cell monolayers in vitro. Conclusions: a synthetic peptide sharing similarity with the putative b2GPI PL-binding site reverses aPL-mediated foetal loss in pregnant naïve mice & inhibits the binding of b2GPI-dependent aPL to human trophoblast & decidual cells. These findings further support the pathogenic role of anti-b2GPI antibodies on aPL-associated fetal loss & offer innovative therapeutic approaches.
|Titolo:||Protective effect of a synthetic peptide mimicking the b2GPI PL-binding site on aPL-induced placental damage|
|Data di pubblicazione:||set-2008|
|Settore Scientifico Disciplinare:||Settore MED/16 - Reumatologia|
|Enti collegati al convegno:||aesku.kipp institute|
|Citazione:||Protective effect of a synthetic peptide mimicking the b2GPI PL-binding site on aPL-induced placental damage / V. Broggini, Y. Martinez de la Torre, E. Raschi, M.O. Borghi, N. Di Simone, M. Nebuloni, A. Vecchi, P. Chen, M. Locati, S.S. Pierangeli, P.L. Meroni. ((Intervento presentato al 6. convegno International congress on autoimmunity tenutosi a Porto nel 2008.|
|Appare nelle tipologie:||14 - Intervento a convegno non pubblicato|