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INFLAMMATION AND IMMUNOPHARMACOLOGY
Inflammation Research Pharmacology Laboratory (T.M., K.S., Y.M., K.T., T.Y., K.T., Y.S.), Medicinal Chemistry Research II Chemistry Laboratory (K.M., I.S.), and Discovery Metabolism Research Analysis and Metabolism Laboratory (M.F.), Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Tsukuba, Japan; and Pharmaceutical Research Laboratories (S.T., Y.T., N.Y., M.K.), Toray Industries, Inc., Kamakura, Japan
Received October 12, 2005; accepted December 7, 2005.
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Abstract |
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; Terada et al., 1994). CCR3, a seven-transmembrane-spanning G protein-coupled receptor, is a major chemokine receptor expressed on allergic inflammatory cells including not only eosinophils but also basophils, mast cells, and T helper 2-type CD4+ cells (Combadiere et al., 1995; Post et al., 1995; Sabroe et al., 1998). This receptor has been identified in humans, monkeys, mice, rats, and guinea pigs (Garcia-Zepeda et al., 1996; Forssmann et al., 1997; Sallusto et al., 1997; Zhang et al., 2002). Human CCR3 binds multiple chemokine ligands such as CCL11/eotaxin, CCL24/eotaxin-2, CCL26/eotaxin-3, and CCL13/MCP-4 with high affinity, whereas CCR3 binds CCL5/regulated on activation normal T cell expressed and secreted and CCL7/MCP-3 with lower affinity (Forssmann et al., 1997; Stellato et al., 1997; Doucet et al., 1998). CCR3 ligands are produced by multiple cell types, including lung and mucosal fibroblast cells, bronchial epithelial cells, vascular endothelial cells, smooth muscle cells, macrophages, mast cells, and eosinophils (Lamkhioued et al., 1997; Lilly et al., 1997; Shinkai et al., 1999; Hirst et al., 2002; Menzies-Gow et al., 2004). The binding of CCR3 ligands to CCR3 on the surface of eosinophils causes a transient increase in intracellular Ca2+ concentration ([Ca2+]i) that activates several signal pathways, including actin polymerization (Elsner et al., 1996). With activation of the intracellular motile apparatus, eosinophils undergo shape change followed by acquisition of a polarized morphology, subsequent migration to sites of allergic inflammation, and granule release to combat against exogenous pathogens and allergens (Elsner et al., 1995; Sambrano and Coughlin, 1999). A characteristic feature of allergic asthma and rhinitis is leukocyte infiltration into the bronchial and intranasal walls, which is predominantly where eosinophils and other CCR3-expressing cells accumulate and are activated (Terada et al., 2001; Sehmi et al., 2003); therefore, CCR3 is an attractive target for treatment of allergic asthma and rhinitis.
Although several nonpeptide compounds that inhibit binding of CCL11 to CCR3 have been reported (Sabroe et al., 2000; White et al., 2000; Saeki et al., 2001; Wan et al., 2002, De Lucca et al., 2005), their in vivo effectiveness has not yet been demonstrated in any nonhuman primates. YM-355179 is a novel, selective, and orally available low-molecular weight CCR3 antagonist that has been chemically synthesized in our laboratories. In this study, the effects of YM-355179 on CCL11-induced chemotaxis, eosinophil degranulation, ex vivo eosinophil shape change, and in vivo eosinophil infiltration into the airways of cynomolgus monkeys were investigated. In vivo effectiveness of YM-355179 indicates the therapeutic potential of CCR3 antagonists for treatment of conditions caused by eosinophilic allergic inflammation, including asthma and allergic rhinitis.
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Materials and Methods |
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). Other CC chemokine receptors were cloned from either a human peripheral blood mononuclear cell cDNA library, human genomic library, or rhesus monkey peripheral blood mononuclear cell library by polymerase chain reaction. Primers were designed based on sequences from the following GenBank submissions: CCR2B (U03905
[GenBank]
), CCR4 (X8540), CCR5 (X91492
[GenBank]
), and monkey CCR3 (AF405537
[GenBank]
). Expression vector pEF-BOS-Neo, carrying each of the full-length receptor cDNA species above, was transfected into B300-19 cells using electroporation; then, G418-resistant stable transformants were isolated (Sato et al., 1999). The transformed B300-19 cells were cultured in RPMI 1640 medium containing 10% fetal bovine serum (FBS), 50 µM 2-mercaptethanol, 1 mg/ml geneticin, 100 U/ml penicillin, and 100 µg/ml streptomycin. cDNA encoding for murine CCR3 (AY049018
[GenBank]
) and rat CCR3 (AF003954
[GenBank]
) was obtained from murine and rat splenocyte mRNA using reverse transcription-polymerase chain reaction and then subcloned into pCR3.1 and pcDNA3.1 vectors, respectively (Invitrogen, Carlsbad, CA). These constructed vectors were then cotransfected with chimeric G protein Gqi5 (Molecular Devices, Sunnyvale, CA) into Chinese hamster ovary (CHO) and human embryonic kidney 293 (HEK293) cells, respectively, using Lipofectamine (Invitrogen). Transfected CHO cells were maintained in 
minimal essential medium supplemented with 10% FBS, 0.25 mg/ml geneticin, 50 U/ml penicillin, and 50 µg/ml streptomycin. Transfected HEK293 cells were maintained in Dulbecco's modified Eagle's medium supplemented with 10% FBS, 50 U/ml penicillin, and 50 µg/ml streptomycin for 24 h before being used for the Ca2+ influx assay.
Binding Assay. Binding assays were performed in 96-well polystyrene microplates (Optiplate-96; PerkinElmer, Wellesley, MA) at 25°C. Cells (3 x 106 cells) were incubated for 60 min in 200 µl of binding buffer [50 mM HEPES, pH 7.5, 1 mM CaCl2, 5 mM MgCl2, and 0.5% bovine serum albumin (BSA)] containing 100 pM 125I-CCL11 or 50 pM 125I-CCL5 and 1 mg/ml wheat germ agglutinin SPA beads (Amersham Pharmacia Biotech, Uppsala, Sweden) in the presence or absence of various concentrations of YM-355179 under constant agitation. Radioactivity was counted using a microplate scintillation counter (TopCount; PerkinElmer). Specific binding of CCL11 or CCL5 to each receptor was defined as the difference between total binding and nonspecific binding obtained in the presence of a 200-fold excess of unlabeled CCL11 or CCL5.
Measurement of [Ca2+]i. Cells were loaded with 5 µM Fura-2 acetoxymethyl ester in RPMI 1640 medium containing 1% BSA for 30 min at 37°C. After being washed twice, cells were resuspended at a concentration of 2 x 106 cells/ml in 20 mM HEPES buffer containing 0.1% BSA, 130 mM NaCl, 5.4 mM KCl, 1 mM MgCl2, 2.5 mM CaCl2, and 5.5 mM glucose. The cell suspension (490 µl) was then transferred into glass cuvettes. One microliter of YM-355179 dimethyl sulfoxide solution was added to the cuvette 1 min prior to addition of various concentrations of chemokine (10 µl). Changes in fluorescence were monitored at 25°C using an intracellular ion analyzer (CAF-110; JASCO, Tokyo, Japan) at 340 and 380 nm (excitation wavelengths) and at 510 nm (emission wavelength). Calculation of [Ca2+]i was performed using Kd for Ca2+ binding at 224 nm.
Chemotaxis Assay. Quantitative chemotaxis assays were performed using 96-well Boyden chambers (Neuro Probe, Gaithersburg, MD) with polyvinylpyrrolidone-free polycarbonate filters with 5-µm pores (Neuro Probe, Gaithersburg, MD) for 3 h at 37°C in a humidified 5% CO2 incubator. Cells suspended at 5 x 106 cells/ml in RPMI 1640 medium containing 0.1% BSA were preincubated for 1 min with various concentrations of either YM-355179 or vehicle (dimethyl sulfoxide), then added to the upper wells (200 µl) without removing compound from the medium. Various concentrations of chemokines were added to the lower wells. Cell numbers migrating to the lower wells were quantified using the ATP-lite (PerkinElmer) bioluminescence assay.
Human Eosinophil Degranulation. CCL11-induced eosinophil degranulation assays were performed as previously described with minor modifications (Kaneko et al., 1995). Human eosinophils were isolated from peripheral blood of normal volunteers. Wells in 96-well flat bottom tissue culture plates (Costar, Cambridge, MA) were blocked with 50 µl of 2.5% BSA diluted in phosphate-buffered saline (PBS) for 2 h at 37°C. After washing, a suspension of 200 µl of eosinophils in RPMI 1640 medium containing 0.5% BSA (5 x 105 cells) with or without 0.6 nM human CCL11 was added to wells and then incubated for 4 h in a humidified incubator at 37°C and 5% CO2 in the presence or absence of various concentrations of YM-355179. After incubation, supernatants were collected and frozen at –20°C until assay for eosinophil-derived neurotoxin (EDN). The amount of released EDN was measured using an enzyme-linked immunosorbent assay kit purchased from MBL International (Woburn, MA).
Animals. Male cynomolgus monkeys (Macaca fascicularis), were imported by Hamuri Co., Ltd. (Sanwa, Japan) and housed individually in stainless steel cages. They were provided with feed twice a day and water ad libitum. Animals used for ex vivo whole blood assays were 3 to 4 years old and weighed from 4 to 7 kg. Animals used for in vivo CCL11-induced eosinophil infiltration were 6 to 8 years old and weighed from 6 to 9 kg.
Cynomolgus Monkey Whole Blood-Gated Autofluorescence Forward Scatter Assay. The procedure for the gated autofluorescence forward scatter (GAFS) assays was modified from that created by Sabroe et al. (1999). Briefly, cynomolgus monkeys were fasted overnight, and either YM-355179 or placebo (distilled water) was administered orally with a gastric tube. At 2, 6, and 12 h after administration, blood samples (80 µl) were collected in polypropylene tubes containing 10 µl of 177 mM citric acid solution, mixed with various concentrations of CCL11 (10 µl), and then incubated at 37°C for 10 min. CCL11-stimulated blood samples were mixed with 2 ml of ice-cold fixative solution containing 2.5% Cell FIX (BD Bioscience, San Jose, CA); then, 2 ml of ice-cold lysis buffer (168 mM NH4Cl and 10 mM KHCO3, pH 7.35) was added to the mixture. After being left on ice for 10 min to achieve uniform red blood cell lysis, remaining white blood cells were washed twice with PBS containing 5% BSA and resuspended in PBS containing 10 mM HEPES, 0.1% 10 mM glucose, and 0.1% BSA. Samples were processed using a FACS Calibur flow cytometer (BD Bioscience), and data from the 20,000 cells contained in each sample were collected. Eosinophils were gated out based on high autofluorescence and mean forward scatter was calculated using CELLQuest software (BD Bioscience).
CCL11-Induced Eosinophil Infiltration into the Airways of Cynomolgus Monkeys. This study was conducted in a placebo-controlled, crossover fashion with 2 weeks interval for washout. Each animal was anesthetized with an intramuscular injection of ketamine hydrochloride (10 mg/kg) and xylazine (1 mg/kg), intubated with a cuffed endotracheal tube, and then placed in the supine position. A pediatric fiberoptic bronchoscope (BF 3C40; Olympus, Tokyo, Japan) was inserted through the cuffed endotracheal tube, guided past the carina, and wedged into a bronchus. CCL11 solution (1 ml; 30 pmol/ml, containing 2% Evans blue) was infused through the lavage channel of the bronchoscope into the bronchus. Each animal received two bolus intravenous injections of YM-355179 or placebo (saline) 5 min before and 24 h after CCL11 provocation to avoid interfering with the absorption of YM-355179 from the gastrointestinal tract, because peristaltic motion was affected by anesthesia. At 48 h after provocation, animals were anesthetized and intubated again with a cuffed endotracheal tube, and then the bronchoscope was inserted into the same bronchus stained with Evans blue. Bronchoalveolar lavage (BAL) was performed through the lavage channel using two 10-ml aliquots of saline. Recovery rate for each BAL fluid sample was approximately the same, about 60%. The BAL fluid was centrifuged at 4°C, and then the sediment was resuspended in 1 ml of saline containing 1 U/ml heparin. Total cell number was counted using an automatic cell counter (Celltac-; Nihon Kohden, Tokyo, Japan). Differential cell counts were performed on slides prepared using a centrifuge (Cytospin 3; Shandon, Pittsburgh, PA) and then stained with Wright-Giemsa stain (Diff-Quik Kit; International Reagents Corporation, Kobe, Japan). A total of 300 cells were counted using standard morphological techniques to calculate the ratio of eosinophil, neutrophil, monocyte, macrophage, lymphocyte, basophil, and mast cells to total leukocytes in the BAL fluid.
Data Analysis. Data were expressed as mean ± S.E.M. Statistical significance of differences between the mean of groups was determined using a paired t test or two-way Dunnett test. Probabilities of <0.05 were considered significant.
Ethical Considerations. All experiments were performed in accordance with the regulations of the Yamanouchi Pharmaceutical Animal Ethics Committee.
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Results |
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protein during CCR3 signal induction, whereas CCL5, CCL7, and CCL26 are only partial agonists (Wan et al., 2002). As shown in Fig. 2A, CCL11, CCL24, CCL26, and CCL13, competitively displaced the binding of 125I-CCL11 to CCR3-expressing B300-19 cells with IC50 values of 1.0, 0.45, 3.2, and 0.052 nM, respectively. CCL5 and CCL7 showed less potent displacement activity (approximately 50% inhibition), even at 100 nM, during the binding of 125I-CCL11 to CCR3. The order of displacement potency (CCL13 > CCL24 > CCL11 > CCL26 » CCL5 = CCL7) using CCR3-expressing B300-19 cells was approximately of the same order as CCR3 ligand affinities for CCR3 on human eosinophils, which was demonstrated during the evaluation of CCR3 agonists (Forssmann et al., 1997; Stellato et al., 1997; Doucet et al., 1998). YM-355179 (Fig. 1) is a novel CCR3 antagonist, chemically synthesized in our laboratories. To demonstrate the effectiveness of YM-355179 in the binding assay, CCL11 and CCL5 were chosen as full and partial agonists, respectively. YM-355179 demonstrated competitive displacement activity during the binding of both 125I-CCL11 and 125I-CCL5 to CCR3 with potent IC50 values of 7.6 and 24 nM, respectively (Fig. 2B). In contrast, YM-355179 did not inhibit the binding of 125I-CCL5 to CCR1 or CCR5, even at a concentration of 10 µM. These results indicate that YM-355179 selectively antagonizes CCR3.
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; Stellato et al., 1997; Doucet et al., 1998). CCL11, CCL24, CCL26, CCL13, and CCL5 showed [Ca2+]i elevation in a concentration-dependent manner (Fig. 3A). EC50 values were 2.4, 4.1, 10, 0.74, and 72 nM, respectively. CCL11 and CCL13 had more potent [Ca2+]i elevation than the other CCR3 ligands CCL24, CCL26, and CCL5. YM-355179 potently inhibited CCL11-, CCL24-, CCL26-, CCL13-, and CCL5-induced [Ca2+]i elevation with IC50 values of 8.0, 5.6, 7.0, 6.1, and 4.5 nM, respectively (Fig. 3B). However, YM-355179 did not affect CCR1-, CCR2-, CCR4-, or CCR5-mediated signals (CCL5-, CCL2-, CCL17-, or CCL5-induced, respectively). Next, the effect of YM-355179 on chemotaxis induced by each CCR3 ligand was examined. All CCR3 ligands tested induced the migration of CCR3-expressing B300-19 cells in a bell-shaped manner, a common feature of all chemokines (Fig. 4A). CCL11 and CCL13 were more potent and effective chemoattractants than the other CCR3 ligands, CCL24, CCL26, and CCL5. YM-355179 inhibited CCL11-, CCL24-, CCL26-, CCL13-, and CCL5-induced chemotaxis with IC50 values of 24, 13, 9.5, 5.9, and 11 nM, respectively (Fig. 4B). No effect was observed on CCR1-, CCR2-, CCR4-, or CCR5-mediated chemotaxis at any YM-355179 concentration, ranging from 0.1 to 10,000 nM (data not shown). The effect of YM-355179 on EDN release was also examined. YM-355179 dose-dependently inhibited EDN release from CCL11-induced human peripheral eosinophils with an IC50 value of 29 nM (Fig. 5). YM-355179 inhibited EDN release at approximately the same concentration as in the Ca2+ influx and chemotaxis assays.
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Effect of YM-355179 on Monkey, Rat, and Murine CCR3. It is important to investigate species specificity of YM-355179 to design in vivo preclinical studies. As shown in Table 1, YM-355179 antagonizes not only human CCR3 but also monkey CCR3. The IC50 value of human CCL11-induced [Ca2+]i elevation in monkey CCR3-expressing B300-19 cells was 12 nM. In contrast, IC50 values of murine CCL11-induced [Ca2+]i elevation in murine CCR3-transfected CHO and rat CCR3-transfected HEK293 cells were 460 nM and greater than 10 µM, respectively. CCR3 antagonistic activity of YM-355179 was less potent in rodents than in primates.
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Pharmacodynamic Analysis of YM-355179 Using Whole Blood GAFS Assay in Cynomolgus Monkeys. Ex vivo whole blood GAFS assay was used to estimate the pharmacodynamics of YM-355179 in monkeys. YM-355179 (1 mg/kg) was orally administered to one monkey; then, whole blood samples were collected 2, 6, and 12 h after the administration. As shown in Fig. 6A, CCL11 (12 and 36 nM)-induced eosinophil shape change in whole blood was observed in the placebo group. In contrast, in blood obtained 2 h after oral administration of YM-355179 (1 mg/kg), CCL11-induced eosinophil shape change was significantly inhibited compared with the placebo group (Fig. 6A). When 12 nM CCL11 was used for stimulation, the inhibitory effect of YM-355179 was maintained up to 12 h after administration (Fig. 6B). When 36 nM CCL11 was used, the effect of YM-355179 was observed at 2 and 6 h after administration.
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In Vivo Effect of YM-355179 on CCL11-Induced Eosinophil Infiltration into the Lung in Cynomolgus Monkeys. The effect of YM-355179 on eosinophil infiltration into the airways of cynomolgus monkeys was investigated. After segmental bronchoprovocation with CCL11, at 48 h a significant increase in total leukocyte number in BAL fluid was observed (Fig. 7A). Cells observed in BAL fluid included eosinophils, basophils, mast cells, lymphocytes, monocytes, macrophages, and neutrophils. Compared with the untreated group, the number of each cell type significantly increased after CCL11 provocation (Fig. 7, A–F). When YM-355179 (1 mg/kg i.v.) was administered twice, 5 min before and 24 h after CCL11 provocation, the number of eosinophils was only 17% of the number in the placebo group, and the difference is statistically significant (Fig. 7B). YM-355179 inhibited not only the number of eosinophils but also the number of lymphocytes, basophils, and mast cells, which are all CCR3-expressing cells, with statistical significance (Fig. 7, C and D). As expected, YM-355179 had no inhibitory effect on the number of non-CCR3-expressing cells such as monocytes, macrophages, and neutrophils in BAL fluid (Fig. 7, E and F).
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Discussion |
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; Ma et al., 2002). The prototype of YM-355179, N-{1-[(6-fluoro-2-naphthyl)methyl]piperidin-4-yl}benzamide (YM-207086) was discovered in our chemical library by high-throughput screening using Ca2+ influx assay with CCR3-expressing B300-19 cells. YM-355179 was approximately 160 times more potent than YM-207086 in the Ca2+ influx assay and inhibited binding of 125I-CCL11 to CCR3. CCR3 ligands such as CCL11, CCL13, and CCL24 play important biological roles in the activation of eosinophils, including inducing shape change, endothelial migration, chemotaxis, and degranulation at the sites of inflammation (Bryan et al., 2002; Zhang et al., 2002). YM-355179 inhibited the binding of 125I-CCL11, CCL11-induced [Ca2+]i elevation, chemotaxis, and EDN release from human eosinophils at approximately the same range of concentration (IC50 = 7.6–29 nM). These results suggest that YM-355179 achieved these inhibitory effects by blocking CCR3. YM-355179 alone did not exhibit agonistic activity similar to CCL11 in chemotaxis or any other functional assays (data not shown).
YM-355179 preferentially inhibited human and monkey CCR3-mediated signals compared with rodent CCR3. Nonpeptide, small molecular, chemokine receptor antagonists sometimes show species specificity (Onuffer et al., 2003). Disparity in the potency of CCR3 antagonism between primates and rodents was more than 60 times based on IC50 values. This is supported by the fact that monkey CCR3 sequence is reportedly 92 to 96% identical to human CCR3 at the amino acid level, whereas murine CCR3 and rat CCR3 show only 67 and 69% homology to human CCR3, respectively (Iino et al., 2002; Zhang et al., 2002). Therefore, cynomolgus monkeys were used for ex vivo and in vivo evaluation of CCR3 antagonism. Oral administration of YM-355179 (1 mg/kg) inhibited CCL11-induced ex vivo eosinophil shape change for an extended period (6–12 h). In pharmacokinetic studies of YM-355179 (1 mg/kg p.o.) in cynomolgus monkeys, mean maximal plasma concentration (Cmax) was 456 ng/ml (907 nM), area under curve(0–24h) was 3198 ng · h/ml, and bioavailability was 67% (data not shown). At 2 h after administration, when ex vivo eosinophil shape change was significantly suppressed, mean plasma concentration was 180.7 ng/ml (359.5 nM), approximately 30 times as much as the IC50 value (12 nM) for monkey CCR3 antagonism in the Ca2+ influx assay. YM-355179 (1 mg/kg i.v.) also inhibited infiltration of eosinophils into the airways of monkeys after segmental bronchoprovocation with CCL11. At 48 h after the first i.v. bolus, when BAL was performed, mean plasma concentration was 72.75 ng/ml (144.8 nM). This concentration is also 10 times higher than the IC50 value obtained for monkey CCR3 antagonism. Ex vivo and in vivo CCR3 antagonistic activities of YM-355179 were supported by sufficient plasma concentrations of the compound in cynomolgus monkeys.
IL-5 plays a primary role in maturation and differentiation of eosinophils in bone marrow, and CCL11 also plays some important roles in their production and migration (Clutterbuck et al., 1989; Peled et al., 1998). CCL11 stimulates differentiation of myelopoietic progenitors to eosinophil precursors to ensure trafficking of immature CD34+ eosinophils from bone marrow into nonhematopoietic tissues such as the intestine and lung mucosal tissues after antigen provocation (Matthews et al., 1998; Peled et al., 1998; Sehmi et al., 2003). CCR3 antagonists are therefore expected to suppress generation of resident immature eosinophils in mucosal tissues during allergic inflammation. CCR3 antagonists like YM-355179 can suppress the function of all CCR3-expressing cells, not only eosinophils but also basophils, mast cells, and CD4+ T helper 2 cells. However, anti-IL-5 antibody will suppress only eosinophils. CCR3 antagonist rather than anti-IL-5 antibody is likely to be useful in the treatment of allergic inflammation.
Anti-CCL11 monoclonal antibody (bertilimumab) is currently being tested in clinical trials for the treatment of seasonal allergic rhinitis. It has shown a tendency to reduce the numbers of submucosal eosinophils and basophils, thus improving postallergy nasal obstruction (Ding et al., 2004). Compared with bertilimumab, CCR3 antagonist YM-355179 demonstrates a more promising effectiveness in the control of allergic diseases because it can inhibit not only CCL11 but also other CCR3 ligands such as CCL24, CCL26, CCL13, and CCL5.
YM-355179 is an attractive novel CCR3 antagonist because of its potency and oral availability. YM-355179 shows good potential as a new therapy for the prevention and treatment of allergic asthma and rhinitis.
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Acknowledgements |
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Footnotes |
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Address correspondence to: Tatsuaki Morokata, Department of Immunology, Pharmacology Research Laboratories, Institute for Drug Discovery Research, Astellas Pharma Inc., 1-6, Kashima 2-Chome, Yodogawa-ku, Osaka 532-8514, Japan. E-mail: tatsuaki.morokata{at}jp.astellas.com
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References |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
Bryan SA, Jose PJ, Topping JR, Wilhelm R, Soderberg C, Kertesz D, Barnes PJ, Williams TJ, Hansel TT, and Sabroe I (2002) Responses of leukocytes to chemokines in whole blood and their antagonism by novel CC-chemokine receptor 3 antagonists. Am J Respir Crit Care Med 165: 1602–1609.
Clutterbuck EJ, Hirst EM, and Sanderson CJ (1989) Human interleukin-5 (IL-5) regulates the production of eosinophils in human bone marrow cultures: comparison and interaction with IL-1, IL-3, IL-6 and GMCSF. Blood 73: 1504–1512.
Combadiere C, Ahuja SK, and Murphy PM (1995) Cloning and functional expression of a human eosinophil CC chemokine receptor. J Biol Chem 270: 16491–16494.[CrossRef][Medline]
De Lucca GV, Kim UT, Vargo BJ, Duncia JV, Santella JB 3rd, Gardner DS, Zheng C, Liauw A, Wang Z, Emmett G, et al. (2005) Discovery of CC chemokine receptor-3 (CCR3) antagonists with picomolar potency. J Med Chem 48: 2194–2211.[CrossRef][Medline]
Ding C, Li J, and Zhang X (2004) Bertilimumab Cambridge Antibody Technology Group. Curr Opin Investig Drugs 5: 1213–1218.[Medline]
Doucet C, Brouty-Boye D, Pottin-Clemenceau C, Canonica GW, Jasmin C, and Azzarone B (1998) Interleukin (IL) 4 and IL-13 act on human lung fibroblasts. Implication in asthma. J Clin Investig 101: 2129–2139.[Medline]
Durham SR and Kay AB (1985) Eosinophils, bronchial hyperreactivity and late-phase asthmatic reactions. Clin Allergy 15: 411–418.[CrossRef][Medline]
Elsner J, Dichmann S, and Kapp A (1995) Activation of the respiratory burst in human eosinophils by chemotaxins requires intracellular calcium fluxes. J Investig Dermatol 105: 231–236.[CrossRef][Medline]
Elsner J, Dichmann S, Dobos GJ, and Kapp A (1996) Actin polymerization in human eosinophils, unlike human neutrophils, depends on intracellular calcium mobilization. J Cell Physiol 167: 548–555.[CrossRef][Medline]
Forssmann U, Uguccioni M, Loetscher P, Dahinden CA, Langen H, Thelen M, and Baggiolini M (1997) Eotaxin-2, a novel CC chemokine that is selective for the chemokine receptor CCR3 and acts like eotaxin on human eosinophil and basophil leukocytes. J Exp Med 185: 2171–2176.
Garcia-Zepeda EA, Rothenberg ME, Ownbey RT, Celestin J, Leder P, and Luster AD (1996) Human eotaxin is a specific chemoattractant for eosinophil cells and provides a new mechanism to explain tissue eosinophilia. Nat Med 2: 449–456.[CrossRef][Medline]
Grimaldi JC, Yu NX, Grunig G, Seymour BW, Cottrez F, Robinson DS, Hosken N, Ferlin WG, Wu X, Soto H, et al. (1999) Depletion of eosinophils in mice through the use of antibodies specific for C-C chemokine receptor 3 (CCR3). J Leukoc Biol 65: 846–853.[Abstract]
Hirst SJ, Hallsworth MP, Peng Q, and Lee TH (2002) Selective induction of eotaxin release by interleukin-13 or interleukin-4 in human airway smooth muscle cells is synergistic with interleukin-1beta and is mediated by the interleukin-4 receptor alpha-chain. Am J Respir Crit Care Med 165: 1161–1171.
Iino T, Sugimoto H, Watanabe A, Encinas JA, Liu N, Floeckner J, and Bacon KB (2002) Molecular cloning and functional characterization of Cynomolgus monkey (Macaca fascicularis) CC chemokine receptor, CCR3. Cytokine 19: 276–286.[CrossRef][Medline]
Kaneko M, Swanson MC, Gleich GJ, and Kita H (1995) Allergen-specific IgG1 and IgG3 through Fc gamma RII induce eosinophil degranulation. J Clin Investig 95: 2813–2821.[Medline]
Lamkhioued B, Renzi PM, Abi-Younes S, Garcia-Zepada EA, Allakhverdi Z, Ghaffar O, Rothenberg MD, Luster AD, and Hamid Q (1997) Increased expression of eotaxin in bronchoalveolar lavage and airways of asthmatics contributes to the chemotaxis of eosinophils to the site of inflammation. J Immunol 159: 4593–4601.[Abstract]
Lilly CM, Nakamura H, Kesselman H, Nagler-Anderson C, Asano K, Garcia-Zepeda EA, Rothenberg ME, Drazen JM, and Luster AD (1997) Expression of eotaxin by human lung epithelial cells: induction by cytokines and inhibition by glucocorticoids. J Clin Investig 99: 1767–1773.[Medline]
Ma W, Bryce PJ, Humbles AA, Laouini D, Yalcindag A, Alenius H, Friend DS, Oettgen HC, Gerard C, and Geha RS (2002) CCR3 is essential for skin eosinophilia and airway hyperresponsiveness in a murine model of allergic skin inflammation. J Clin Investig 109: 621–628.[CrossRef][Medline]
Matthews AN, Friend DS, Zimmermann N, Sarafi MN, Luster AD, Pearlman E, Wert SE, and Rothenberg ME (1998) Eotaxin is required for the baseline level of tissue eosinophils. Proc Natl Acad Sci USA 95: 6273–6278.
Menzies-Gow A, Ying S, Phipps S, and Kay AB (2004) Interactions between eotaxin, histamine and mast cells in early microvascular events associated with eosinophil recruitment to the site of allergic skin reactions in humans. Clin Exp Allergy 34: 1276–1282.[CrossRef][Medline]
Onuffer J, McCarrick MA, Dunning L, Liang M, Rosser M, Wei GP, Ng H, and Horuk R (2003) Structure function differences in nonpeptide CCR1 antagonists for human and mouse CCR1. J Immunol 170: 1910–1916.
Peled A, Gonzalo JA, Lloyd C, and Gutierrez-Ramos JC (1998) The chemotactic cytokine eotaxin acts as a granulocyte-macrophage colony-stimulating factor during lung inflammation. Blood 91: 1909–1916.
Post TW, Bozic CR, Rothenberg ME, Luster AD, Gerard N, and Gerard C (1995) Molecular characterization of two murine eosinophil beta chemokine receptors. J Immunol 155: 5299–5305.[Abstract]
Sabroe I, Conroy DM, Gerard NP, Li Y, Collins PD, Post TW, Jose PJ, Williams TJ, Gerard CJ, and Ponath PD (1998) Cloning and characterization of the guinea pig eosinophil eotaxin receptor, C-C chemokine receptor-3: blockade using a monoclonal antibody in vivo. J Immunol 161: 6139–6147.
Sabroe I, Hartnell A, Jopling LA, Bel S, Ponath PD, Pease JE, Collins PD, and Williams TJ (1999) Differential regulation of eosinophil chemokine signaling via CCR3 and non-CCR3 pathways. J Immunol 162: 2946–2955.
Sabroe I, Peck MJ, Van Keulen BJ, Jorritsma A, Simmons G, Clapham PR, Williams TJ, and Pease JE (2000) A small molecule antagonist of chemokine receptors CCR1 and CCR3. J Biol Chem 275: 25985–25992.
Saeki T, Ohwaki K, Naya A, Kobayashi K, Ishikawa M, Ohtake N, and Noguchi K (2001) Identification of a potent and nonpeptidyl CCR3 antagonist. Biochem Biophys Res Commun 281: 779–782.[CrossRef][Medline]
Sallusto F, Mackay CR, and Lanzavecchia A (1997) Selective expression of the eotaxin receptor CCR3 by human T helper 2 cells. Science (Wash DC) 277: 2005–2007.
Sambrano GR and Coughlin SR (1999) The carboxyl tail of protease-activated receptor-1 is required for chemotaxis. Correlation of signal termination and directional migration. J Biol Chem 274: 20178–20184.
Sato K, Kawasaki H, Nagayama H, Serizawa R, Ikeda J, Morimoto C, Yasunaga K, Yamaji N, Tadokoro K, Juji T, et al. (1999) CC chemokine receptors, CCR-1 and CCR-3, are potentially involved in antigen-presenting cell function of human peripheral blood monocyte-derived dendritic cells. Blood 93: 34–42.
Sehmi R, Dorman S, Baatjes A, Watson R, Foley R, Ying S, Robinson DS, Kay AB, O'Byrne PM, and Denburg JA (2003) Allergen-induced fluctuation in CC chemokine receptor 3 expression on bone marrow CD34+ cells from asthmatic subjects: significance for mobilization of haemopoietic progenitor cells in allergic inflammation. Immunology 109: 536–546.[CrossRef][Medline]
Shinkai A, Yoshisue H, Koike M, Shoji E, Nakagawa S, Saito A, Takeda T, Imabeppu S, Kato Y, Hanai N, et al. (1999) A novel human CC chemokine, eotaxin-3, which is expressed in IL-4-stimulated vascular endothelial cells, exhibits potent activity toward eosinophils. J Immunol 163: 1602–1610.
Stellato C, Collins P, Ponath PD, Soler D, Newman W, La Rosa G, Li H, White J, Schwiebert LM, Bickel C, et al. (1997) Production of the novel C-C chemokine MCP-4 by airway cells and comparison of its biological activity to other C-C chemokines. J Clin Investig 99: 926–936.[Medline]
Terada N, Hamano N, Kim WJ, Hirai K, Nakajima T, Yamada H, Kawasaki H, Yamashita T, Kishi H, Nomura T, et al. (2001) The kinetics of allergen-induced eotaxin level in nasal lavage fluid: its key role in eosinophil recruitment in nasal mucosa. Am J Respir Crit Care Med 164: 575–579.
Terada N, Konno A, and Togawa K (1994) Biochemical properties of eosinophils and their preferential accumulation mechanism in nasal allergy. J Allergy Clin Immunol 94: 629–642.[CrossRef][Medline]
Wan Y, Jakway JP, Qiu H, Shah H, Garlisi CG, Tian F, Ting P, Hesk D, Egan RW, Billah MM, et al. (2002) Identification of full, partial and inverse CC chemokine receptor 3 agonists using [35S]GTP
S binding. Eur J Pharmacol 456: 1–10.[CrossRef][Medline]
White JR, Lee JM, Dede K, Imburgia CS, Jurewicz AJ, Chan G, Fornwald JA, Dhanak D, Christmann LT, Darcy MG, et al. (2000) Identification of potent, selective non-peptide CC chemokine receptor-3 antagonist that inhibits eotaxin-, eotaxin-2- and monocyte chemotactic protein-4-induced eosinophil migration. J Biol Chem 275: 36626–36631.
Zhang L, Soares MP, Guan Y, Matheravidathu S, Wnek R, Johnson KE, Meisher A, Iliff SA, Mudgett JS, Springer MS, et al. (2002) Functional expression and characterization of macaque C-C chemokine receptor 3 (CCR3) and generation of potent antagonistic anti-macaque CCR3 monoclonal antibodies. J Biol Chem 277: 33799–33810.
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