International Immunology Advance Access originally published online on June 18, 2007
International Immunology 2007 19(7):857-865; doi:10.1093/intimm/dxm052
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The efficacy of specific IVIG anti-idiotypic antibodies in antiphospholipid syndrome (APS): trophoblast invasiveness and APS animal model
1 The Autoimmune Disease Center, Sheba Medical Center
2 Department of Human Microbiology, Sackler Faculty of Medicine, Tel-Aviv University, Israel
3 Department of Medicine B, Sheba Medical Center, Tel-Hashomer and Sackler faculty of Medicine, Tel-Aviv university, Israel
4 Laboratory for Research in Reproductive Sciences, Department of Obstetrics and Gynecology, Ha’Emek Medical Center, Afula, Israel
5 Department of Autoimmune Diseases, Institute Clinic de Medicina i Dermatologia, Hospital Clinic, Barcelona, Catalonia, Spain
6 Department of Organic Chemistry, The Weizman Institute for Sciences, Rehovot, Israel
7 Department of Immunology, University of Rostock, Schillingallee 70, 18055 Rostock, Germany
8 Incumbent of the Laura Schwarz-Kipp Chair for Research of Autoimmune Diseases, Tel-Aviv University, Israel
Correspondence to: Y. Shoenfeld; E-mail: shoenfel{at}post.tau.ac.il
Objectives: Administration of intravenous Ig (IVIG) is a recognized, safe and efficient mode of immunomodulatory therapy for many autoimmune diseases. Anti-idiotypic antibody binding to pathogenic autoantibodies and hence inhibition of binding to the corresponding antigen is one postulated mechanism of the beneficial effect of IVIG. The aim of this study was to fractionate the anti-beta-2-glycoprotein-I (ß2GPI) anti-idiotypic antibodies from a commercial IVIG preparation and use it as a treatment in an experimental antiphospholipid syndrome (APS) mouse model. Methods: Anti-ß2GPI polyclonal antibodies were purified on a ß2GPI column. The purified antibodies were bound to CN–Br-activated sepharose and employed for purification of IVIG-anti-anti-ß2GPI (anti-idiotypic antibodies), defined as specific intravenous Ig (sIVIG). The idiotype specificities were confirmed by competition assays. The effect of sIVIG in vitro was tested in a trophoblast and choriocarcinoma matrigel/invasion assay (i.e. proliferation and metalloproteinase (MMP)2/MMP9 expression) and in vivo in a fetal loss model of APS. Results: Anti-ß2GPI antibodies inhibited human trophoblast cell invasion in vitro. The function was attributed to the Fab portion of the anti-ß2GPI Igs, since ß2GPI-related synthetic peptides specific for the Fab part of the anti-ß2GPI antibodies neutralized its activity. APS sIVIG fraction reduce human trophoblast invasion in vitro by 560 times more than the whole IVIG compound and improved the MMP2 and MMP9 production by trophoblast cells. sIVIG improved significantly (200 times more) the pregnancy outcome in BALB/c mice passively infused with anti-ß2GPI antibodies, in comparison to treatment with IVIG (P < 0.02). Conclusions: Based on the current results, we propose that APS sIVIG may be considered as potential specific therapeutic safe compound for developing a treatment for APS patient's early fetal loss.
Keywords: antiphospholipid syndrome, autoantibodies, beta-2-glycoprotein-I, experimental model, IVIG
Transmitting editor: I. Pecht
Received 27 September 2006, accepted 17 April 2007.
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