Monoclonal antibody blockade of L-selectin inhibits mononuclear leukocyte recruitment to inflammatory sites in vivo.
L-selectin interacting with inducible endothelial counterreceptors mediates in part the initial adhesive interactions, termed rolling, between circulating blood leukocytes and vascular endothelium. While blockade of L-selectin function in in vivo models of inflammation reduces both neutrophil and lymphocyte influx at early times, little is known concerning the role of L-selectin in leukocyte recruitment at later times (> 24 hours). Using an in vivo murine model of experimentally induced inflammation of the peritoneum, the role of L-selectin in recruitment of mononuclear leukocytes to chronic sites of inflammation (48 hours) was investigated. Saturating levels of function blocking anti-L-selectin monoclonal antibody (MEL-14) or control rat IgG were maintained for 48 hours using surgically implanted mini-osmotic pumps; this treatment did not alter the circulating leukocyte cell count or differential. In animals receiving MEL-14 monoclonal antibody (MAb), macrophage and lymphocyte accumulation in response to thioglycollate was reduced by 60% (P < or = 0.0002) and > 90% (P < 0.001), respectively, at 48 hours as compared with animals implanted with pumps containing saline. Similarly, MEL-14 MAb dramatically inhibited granulocyte influx by 80% (P < 0.03) at 6 hours; recruitment at 24 and 48 hours was reduced by 50%. In contrast, the effects of purified rat IgG was not significantly different from saline. Our results suggest L-selectin, interacting with its inducible endothelial counterreceptor(s), plays an important role in circulating mononuclear leukocyte extravasation at sites of inflammation.
Pizcueta
P
P
Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115.
Luscinskas
F W
FW
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D002448:Cell Adhesion / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000276:immunology*; D002465:Cell Movement / Q000187:drug effects; D005260:Female; D007249:Inflammation / Q000473:pathology / Q000503:physiopathology*; D019041:L-Selectin; D008214:Lymphocytes / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000502:physiology*; D009504:Neutrophils / Q000502:physiology
D000911:Antibodies, Monoclonal; D015815:Cell Adhesion Molecules; D019041:L-Selectin