Chemokine receptor usage by human eosinophils. The importance of CCR3 demonstrated using an antagonistic monoclonal antibody.
Chemokines bind and signal through G-protein coupled seven transmembrane receptors. Various chemokine receptors are expressed on leukocytes, and these may impart selective homing of leukocyte subsets to sites of inflammation. Human eosinophils express the eotaxin receptor, CCR3, but respond to a variety of CC chemokines apart from eotaxin, including RANTES, monocyte chemotactic protein (MCP)-2, MCP-3, and MCP-4. Here we describe a mAb, 7B11, that is selective for CCR3 and has the properties of a true receptor antagonist. 7B11 blocked binding of various radiolabeled chemokines to either CCR3 transfectants, or eosinophils. Pretreatment of eosinophils with this mAb blocked chemotaxis and calcium flux induced by all CCR3 ligands. In all individuals examined, including allergic and eosinophilic donors, > 95% of the response of eosinophils to eotaxin, RANTES, MCP-2, MCP-3, and MCP-4 was shown to be mediated through CCR3. The IL-8 receptors, particularly CXCR2, were induced on IL-5 primed eosinophils, however these eosinophils responded to CC chemokines in the same manner as unprimed eosinophils. These results demonstrate the importance of CCR3 for eosinophil responses, and the feasibility of completely antagonizing this receptor.
Heath
H
H
LeukoSite, Inc., Cambridge, Massachusetts 02142, USA.
Qin
S
S
Rao
P
P
Wu
L
L
LaRosa
G
G
Kassam
N
N
Ponath
P D
PD
Mackay
C R
CR
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D054413:Chemokine CCL11; D018946:Chemokine CCL5 / Q000037:antagonists & inhibitors / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism*; D019742:Chemokines, CC; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000378:metabolism; D004804:Eosinophils / Q000378:metabolism*; D006801:Humans; D015848:Interleukin-5 / Q000378:metabolism; D018945:Monocyte Chemoattractant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D054397:Receptors, CCR3; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D018123:Receptors, Interleukin / Q000378:metabolism; D023062:Receptors, Interleukin-8A
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; C515456:CCL11 protein, human; C515350:CCR3 protein, human; D054413:Chemokine CCL11; D018946:Chemokine CCL5; D018925:Chemokines; D019742:Chemokines, CC; D016207:Cytokines; D015848:Interleukin-5; D018945:Monocyte Chemoattractant Proteins; D054397:Receptors, CCR3; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine; D018123:Receptors, Interleukin; D023062:Receptors, Interleukin-8A; D002118:Calcium