The human specific CCR1 antagonist CP-481,715 inhibits cell infiltration and inflammatory responses in human CCR1 transgenic mice.
We previously described the in vitro characteristics of the potent and selective CCR1 antagonist, CP-481,715. In addition to being selective for CCR1 vs other chemokine receptors, CP-481,715 is also specific for human CCR1 (hCCR1), preventing its evaluation in classical animal models. To address this, we generated mice whereby murine CCR1 was replaced by hCCR1 (knockin) and used these animals to assess the anti-inflammatory properties of CP-481,715. Cells isolated from hCCR1 knockin mice were shown to express hCCR1 and migrate in response to both murine CCR1 and hCCR1 ligands. Furthermore, this migration is inhibited by CP-481,715 at dose levels comparable to those obtained with human cells. In animal models of cell infiltration, CP-481,715 inhibited CCL3-induced neutrophil infiltration into skin or into an air pouch with an ED50 of 0.2 mg/kg. CP-481,715 did not inhibit cell infiltration in wild-type animals expressing murine CCR1. In a more generalized model of inflammation, delayed-type hypersensitivity, CP-481,715 significantly inhibited footpad swelling and decreased the amount of IFN-gamma and IL-2 produced by isolated spleen cells from sensitized animals. It did not, however, induce tolerance to a subsequent challenge. These studies illustrate the utility of hCCR1 knockin animals to assess the activity of human specific CCR1 antagonists; demonstrate the ability of the CCR1 antagonist CP-481,715 to inhibit cell infiltration, inflammation, and Th1 cytokine responses in these animals; and suggest that CP-481,715 may be useful to modulate inflammatory responses in human disease.
Pfizer Global Research and Development, Department of Immunology, Groton, CT 06340, USA. Ronald.P.Gladue@Pfizer.com
Ronald P
RP
Gladue
Susan H
SH
Cole
Marsha L
ML
Roach
Laurie A
LA
Tylaska
Robin T
RT
Nelson
Richard M
RM
Shepard
John D
JD
McNeish
Kevin T
KT
Ogborne
Kuldeep S
KS
Neote
D000199:Actins / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002464:Cell Migration Inhibition; D002478:Cells, Cultured; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019742:Chemokines, CC / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects* / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D019402:Macrophage Inflammatory Proteins / Q000502:physiology; D051379:Mice; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D011810:Quinoxalines / Q000494:pharmacology*; D054389:Receptors, CCR1; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000235:genetics*; D013234:Stem Cells / Q000276:immunology / Q000473:pathology; D018417:Th1 Cells / Q000187:drug effects / Q000378:metabolism
D000199:Actins; D000894:Anti-Inflammatory Agents, Non-Steroidal; C515300:CCR1 protein, human; C496534:Ccl3 protein, mouse; C515301:Ccr1 protein, mouse; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019742:Chemokines, CC; D016207:Cytokines; D019402:Macrophage Inflammatory Proteins; D011810:Quinoxalines; D054389:Receptors, CCR1; D019707:Receptors, Chemokine; C479133:quinoxaline-2-carboxylic acid (4-carbamoyl-1-(3-fluorobenzyl)-2,7-dihydroxy-7-methyloctyl)amide