Antibodies against the first Ig-like domain of human platelet endothelial cell adhesion molecule-1 (PECAM-1) that inhibit PECAM-1-dependent hemophilic adhesion block in vivo neutrophil recruitment

Platelet endothelial cell adhesion molecule (PECAM-1), a member of the Ig s uperfamily, is found on endothelial cells and neutrophils and has been show n to be involved in the migration of leukocytes across the endothelium, Adh esion is mediated, at least in part, through binding interactions involving its first N-terminal Ig-like domain, but it is still unclear which sequenc es in this domain are required for in vivo function, Therefore, to identify functionally important regions of the first Ig-like domain of PECAM-1 that are required for the participation of PECAM-1 in in vivo neutrophil recrui tment, a panel of mAbs against this region of PECAM-1 was generated and cha racterized in in vitro adhesion assays and in an in vivo model of cutaneous inflammation, It was observed that mAbs that disrupted PECAM-1-dependent h emophilic adhesion in an L cell aggregation assay also blocked TNF-alpha-in duced intradermal accumulation of neutrophils in a transmigration model usi ng human skin transplanted onto SCID mice. Localization of the epitopes of these Abs indicated that these function-blocking Abs mapped to specific reg ions on either face of domain 1, This suggests that these regions of the fi rst Ig-like domain may contain or be close to binding sites involved in PEC AM-1-dependent hemophilic adhesion, and thus may represent potential target s for the development of antiinflammatory reagents.