Selective inhibition of eosinophil influx into the lung by small molecule CC chemokine receptor 3 antagonists in mouse models of allergic inflammation.
CC chemokine receptor (CCR) 3 is a chemokine receptor implicated in recruiting cells, particularly eosinophils (EPhi), to the lung in episodes of allergic asthma. To investigate the efficacy of selective, small molecule antagonists of CCR3, we developed a murine model of EPhi recruitment to the lung. Murine eotaxin was delivered intranasally to mice that had previously received i.p. injections of ovalbumin (OVA), and the effects were monitored by bronchoalveolar lavage. A selective eosinophilic influx was produced in animals receiving eotaxin but not saline. Furthermore, the number of EPhi was concentration- and time-dependent. Although anti-CCR3 antibody reduced the number of EPhi, the effect of eotaxin in OVA-sensitized mice was not a direct chemotactic stimulus because mast cell deficiency (in WBB6F1-Kitw/Kitw-v mice) significantly reduced the response. Two representative small molecule CCR3 antagonists from our program were characterized as being active at mouse CCR3. They were administered p.o. to wild-type mice and found to reduce eotaxin-elicited EPhi selectively in a dose-dependent manner. Pump infusion of one of the inhibitors to achieve steady-state levels showed that efficacy was not achieved at plasma concentrations equivalent to the in vitro chemotaxis IC90 but only at much higher concentrations. To extend the results from our recruitment model, we tested one of the inhibitors in an allergenic model of airway inflammation, generated by adoptive transfer of OVA-sensitive murine T helper 2 cells and aerosolized OVA challenge of recipient mice, and found that it inhibited EPhi recruitment. We conclude that small molecule CCR3 antagonists reduce pulmonary eosinophilic inflammation elicited by chemokine or allergenic challenge.
Das
Anuk M
AM
Department of Immunology, Bristol Myers Squibb Co., P.O. Box 4000, Mail code K24-09, Princeton, NJ 08543-4000, USA.
Vaddi
Krishna G
KG
Solomon
Kimberly A
KA
Krauthauser
Candice
C
Jiang
Xiaosui
X
McIntyre
Kim W
KW
Yang
Xiao Xia
XX
Wadman
Eric
E
Welch
Patricia
P
Covington
Maryanne
M
Graden
Danielle
D
Yeleswaram
Krishnaswamy
K
Trzaskos
James M
JM
Newton
Robert C
RC
Mandlekar
Sandhya
S
Ko
Soo S
SS
Carter
Percy H
PH
Davies
Paul
P
D000818:Animals; D016466:CHO Cells; D002464:Cell Migration Inhibition; D006224:Cricetinae; D004195:Disease Models, Animal; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D012130:Respiratory Hypersensitivity / Q000276:immunology / Q000378:metabolism*
C515350:CCR3 protein, human; C515351:Ccr3 protein, mouse; D054397:Receptors, CCR3; D019707:Receptors, Chemokine