Prevention of experimental antiphospholipid syndrome and endothelial cell activation by synthetic peptides

Miri Blank, Yehuda Shoenfeld, Shmuel Cabilly, Yehudit Heldmani, Mati Fridkin, Ephraim Katchalski-Katzir

Research output: Contribution to journalArticlepeer-review

Abstract

Antiphospholipid syndrome (APS) is characterized by recurrent fetal loss, repeated thromboembolic phenomena, and thrombocytopenia. The syndrome is believed to be caused by antiphospholipid beta-2-glycoprotein-I (β2GPI)- dependent Abs or anti-β2GPI Abs by themselves. Using a hexapeptide phage display library, we identified three hexapeptides that react specifically with the anti-β2GPI mAbs ILA-1, ILA-3, and H-3, which cause endothelial cell activation and induce experimental APS. To enhance the binding of the peptides to the corresponding mAbs, the peptides were lengthened to correspond with the site of the β2GPI epitope being recognized by these mAbs. As a result, the following three peptides were prepared: A, NTLKTPRVGGC, which binds to ILA-1 mAb; B, KDKATFGCHDGC, which binds to ILA-3 mAb; and C, CATLRVYKGG, which binds to H-3 mAb. Peptides A, B, and C specifically inhibit both in vitro and in vivo the biological functions of the corresponding anti-β2GPI mAbs. Exposure of endothelial cells to anti- β2GPI mAbs and their corresponding peptides led to the inhibition of endothelial cell activation, as shown by decreased expression of adhesion molecules (E-selectin, ICAM-1, VCAM-1) and monocyte adhesion. In vivo infusion of each of the anti-β2GPI mAbs into BALB/c mice, followed by administration of the corresponding specific peptides, prevented the peptide- treated mice from developing experimental APS. The use of synthetic peptides that focus on neutralization of pathogenic anti-β2GPI Abs represents a possible new therapeutic approach to APS.

Original languageEnglish
Pages (from-to)5164-5168
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume96
Issue number9
DOIs
StatePublished - 27 Apr 1999

Keywords

  • Anti-βglycoprotein-I
  • Anticardiolipin
  • Peptide phage display library

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