Inhibition of T cell recruitment and cutaneous delayed-type hypersensitivity-induced inflammation with antibodies to monocyte chemoattractant protein-1.
Leukocytes express chemokine receptors that, upon ligand recognition, are believed to activate and induce the directed migration of these cells from the vasculature to sites of tissue injury. Previous investigations of human and animal inflammatory tissue have revealed that expression of chemokines can be increased in association with leukocyte infiltration. Monocyte chemotactic protein-1 (MCP-1) mediates monocyte chemotaxis in vitro and migration of monocytes to inflammatory sites in vivo. More recently T cell chemotaxis to MCP-1 has been observed in vitro, but the contribution of this protein to T cell migration in vivo and to lymphocyte-mediated inflammation has not been determined. In this report, we show that using a rat model of cutaneous delayed hypersensitivity, MCP-1 expression correlates spatially and kinetically with T cell and monocyte recruitment and that antibodies directed to MCP-1 when administered therapeutically to animals undergoing delayed hypersensitivity can almost completely abolish T cell migration and inflammatory sequelae. Moreover the concentration of antibody needed to inhibit T cell trafficking to inflammatory sites is almost on order of magnitude lower than that needed to impede monocyte recruitment. Therefore, MCP-1 is functionally relevant in the genesis of delayed hypersensitivity and may be a useful therapeutic target for diseases mediated in part by T lymphocytes.
Rand
M L
ML
Experimental Therapeutics Group, LeukoSite Inc., Cambridge, Massachusetts 02142, USA.
Warren
J S
JS
Mansour
M K
MK
Newman
W
W
Ringler
D J
DJ
D000818:Animals; D000906:Antibodies / Q000276:immunology*; D002465:Cell Movement / Q000502:physiology; D018932:Chemokine CCL2 / Q000276:immunology* / Q000378:metabolism; D003877:Dermatitis, Contact / Q000473:pathology*; D006968:Hypersensitivity, Delayed / Q000473:pathology*; D008297:Male; D009000:Monocytes / Q000502:physiology; D009504:Neutrophils / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D011917:Rats, Inbred Lew; D013601:T-Lymphocytes / Q000502:physiology*; D014018:Tissue Distribution
D000906:Antibodies; D018932:Chemokine CCL2