Anti-phospholipid induced murine fetal loss: Novel protective effect of a peptide targeting the 尾2 glycoprotein I phospholipid-binding site. Implications for human fetal loss

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• 作者：Yeny Martinez de la Torre^a ; ¹ ; Francesca Pregnolato^b ; Fabio D&rsquo ; Amelio^c ; Claudia Grossi^b ; Nicoletta Di Simone^d ; Fabio Pasqualini^e ; Manuela Nebuloni^f ; Pojen Chen^g ; Silvia Pierangeli^h ; Niccolò ; Bassaniⁱ ; Federico Ambrogiⁱ ; Maria-Orietta Borghi^b ; ^c ; Annunciata Vecchi^e ; Massimo Locati^a ; ^j ; Pier-Luigi Meroni^b ; ^c ; ^k ; ^{pierluigi.meroni@unimi.it}
• 关键词：Anti-phospholipid syndrome ; Pregnancy complications ; 尾2 glycoprotein I ; Murine models ; TIFI
• 刊名：Journal of Autoimmunity
• 出版年：2012
• 期刊代码：101_08968411
• 类别：imm
• 出版时间：May, 2012
• 卷：38
• 期：2-3
• 页码：J209-J215
• 文件大小：1105 K

摘要

尾2 glycoprotein I (尾2GPI)-dependent anti-phospholipid antibodies (aPL) induce thrombosis and affect pregnancy. The CMV-derived synthetic peptide TIFI mimics the PL-binding site of 尾2GPI and inhibits 尾2GPI cell-binding in聽vitro and aPL-mediated thrombosis in聽vivo. Here we investigated the effect of TIFI on aPL-induced fetal loss in mice. TIFI inhibitory effect on in聽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聽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.