期刊论文详细信息
Respiratory Research
Protective effect of a Protein Epitope Mimetic CCR10 antagonist, POL7085, in a model of allergic eosinophilic airway inflammation
Nelly Frossard1  Eric Chevalier2  Garry J. Douglas2  Françoise Jung2  François Daubeuf1 
[1] Laboratoire d’Innovation Thérapeutique, Unité Mixte de Recherche 7200, Centre National de la Recherche Scientifique-Université de Strasbourg and LabEx Medalis, Faculté de Pharmacie, 74, route du Rhin, Illkirch, 67400, France;Polyphor Ltd, Hegenheimermattweg 125, Allschwil, CH-4123, Switzerland
关键词: Eosinophilia;    Ovalbumin;    Allergen;    Mouse;    Inflammation;    Airway hyperresponsiveness;    Asthma;    CCL28;    CCR10;   
Others  :  1233540
DOI  :  10.1186/s12931-015-0231-5
 received in 2015-01-08, accepted in 2015-06-08,  发布年份 2015
【 摘 要 】

Background

Potential involvement of the CCR10/CCL28 axis was recently reported in murine models of allergic asthma. If confirmed, blockade of the CCR10 receptor would represent an alternative to current asthma therapies. We evaluated the effect of a novel Protein Epitope Mimetic CCR10 antagonist, POL7085, in a murine model of allergic eosinophilic airway inflammation.

Methods

Mice were sensitized and challenged to ovalbumin. POL7085, a CCR10 antagonist (7.5 and 15 mg/kg), dexamethasone (1 mg/kg) or vehicle were administered intranasally once daily 1h before each allergen challenge. On day 21, airway hyperresponsiveness, bronchoalveolar lavage inflammatory cells and Th2 cytokines, and lung tissue mucus and collagen were measured.

Results

Allergen challenge induced airway hyperresponsiveness in vehicle-treated animals as measured by whole body barometric plethysmography, and eosinophilia in bronchoalveolar lavage. POL7085 dose-dependently and significantly decreased airway hyperresponsiveness (34 ± 16 %) and eosinophil numbers in bronchoalveolar lavage (66 ± 6 %). In addition, the highest dose of POL7085 used significantly inhibited lung IL-4 (85 ± 4 %), IL-5 (87 ± 2 %) and IL-13 (190 ± 19 %) levels, and lung collagen (43 ± 11 %).

Conclusions

The Protein Epitope Mimetic CCR10 antagonist, POL7085, significantly and dose-dependently decreased allergen-induced airway hyperresponsiveness and airway inflammation after once daily local treatment. Our data give strong support for further investigations with CCR10 antagonists in asthmatic disease.

【 授权许可】

   
2015 Daubeuf et al.

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【 参考文献 】
  • [1]English K, Brady C, Corcoran P, Cassidy JP, Mahon BP. Inflammation of the respiratory tract is associated with CCL28 and CCR10 expression in a murine model of allergic asthma. Immunol Lett. 2006; 103:92-100.
  • [2]John AE, Thomas MS, Berlin AA, Lukacs NW. Temporal production of CCL28 corresponds to eosinophil accumulation and airway hyperreactivity in allergic airway inflammation. Am J Pathol. 2005; 166:345-53.
  • [3]O’Gorman MT, Jatoi NA, Lane SJ, Mahon BP. Il-1βand TNFα induce increased expression of CCL28 by airway epithelial cells via an NFkB-dependent pathway. Cell Immunol. 2005; 238:87-96.
  • [4]Holtzman MJ, Byers DE, Benoit LA, Battaile JT, You Y, Agapov E et al.. Immune pathways for translating viral infection into chronic airway disease. Adv Immunol. 2009; 102:245-76.
  • [5]Jarmin DI, Rits M, Bota D, Gerard NP, Graham GJ, Clark-Lewis I et al.. Identification of the orphan receptor G-protein-coupled receptor 2 as CCR10, a specific receptor for the chemokine ESkine. J Immunol. 2000; 164:3460-4.
  • [6]Homey B, Wang W, Soto H, Buchanan ME, Wiesenborn A, Catron D et al.. The orphan chemokine receptor G protein-coupled receptor-2 (GPR2, CCR10) binds the skin-associated chemokine CCL27 (CTACK/ALP/ILC). J Immunol. 2000; 164:3465-70.
  • [7]Kunkel EJ, Kim CH, Lazarus NH, Vierra MA, Soler D, Bowman EP et al.. CCR10 expression is a common feature of circulating and mucosal epithelial tissue IgA Ab-secreting cells. J Clin Invest. 2003; 111:1001-10.
  • [8]Xiong N, Fu Y, Hu S, Xia M, Yang J. CCR10 and its ligands in regulation of epithelial immunity and diseases. Protein Cell. 2012; 3:571-80.
  • [9]Wang W, Soto H, Oldham ER, Buchanan ME, Homey B, Catron D et al.. Identification of a novel chemokine (CCL28), which binds CCR10 (GPR2). J Biol Chem. 2000; 275:22313-23.
  • [10]Pan J, Kunkel EJ, Gosslar U, Lazarus N, Langdon P, Broadwell K et al.. A novel chemokine ligand for CCR10 and CCR3 expressed by epithelial cells in mucosal tissues. J Immunol. 2000; 165:2943-9.
  • [11]Hieshima K, Ohtani H, Shibano M, Izawa D, Nakayama T, Kawasaki Y et al.. CCL28 has dual roles in mucosal immunity as a chemokine with broad-spectrum antimicrobial activity. J Immunol. 2003; 170:1452-61.
  • [12]Homey B, Alenius H, Müller A, Soto H, Bowman EP, Yuan W et al.. CCL27-CCR10 interactions regulate T cell-mediated skin inflammation. Nat Med. 2002; 8:157-65.
  • [13]Scanlon KM, Hawksworth RJ, Lane SJ, Mahon BP. IL-17A induces CCL28, supporting the chemotaxis of IgE-secreting B cells. Int Arch Allergy Immunol. 2011; 156:51-61.
  • [14]Berri M, Virlogeux-Payant I, Chevaleyre C, Melo S, Zanello G, Salmon H et al.. CCL28 involvement in mucosal tissues protection as a chemokine and as an antibacterial peptide. Dev Comp Immunol. 2014; 44:286-90.
  • [15]Alvarez D, Arkinson JL, Sun J, Fattouh R, Walker T, Jordana M. Th2 differentiation in distinct lymph nodes influences the site of mucosal Th2 immune-inflammatory response. J Immunol. 2007; 179:3287-96.
  • [16]Robinson JA, DeMarco S, Gombert F, Moehle K, Obrecht D. The design, structures and therapeutic potential of protein epitope mimetics. Drug Discov Today. 2008; 13:944-51.
  • [17]Jung F, Gombert FO, Obrecht D, Bisang C, Barthelemy S, Lederer A, et al. Template-fixed peptidomimetics with CCR10 antagonistic activity. WO/2011/060937.
  • [18]Daubeuf F, Frossard N. Acute Ovalbumin asthma model in the mouse. Curr Protoc Mouse Biol. 2013; 3:31-7.
  • [19]Hamelmann E, Schwarze J, Takeda K, Oshiba A, Larsen LG, Irvin CG et al.. Noninvasive measurement of airway responsiveness in allergic mice using barometric plethysmography. Am J Respir Crit Care Med. 1997; 156:766-75.
  • [20]Daubeuf F, Reber L, Frossard N. Measurement of airway responsiveness on vigil and unrestrained mouse. Bio-protocols. 2013; 2:20.
  • [21]Daubeuf F, Frossard N. Performing bronchoalveolar lavage in the mouse. Curr Protoc Mouse Biol. 2012; 2:167-75.
  • [22]Grayson MH, Cheung D, Rohlfing MM, Kitchens R, Spiegel DE, Tucker J et al.. Induction of high-affinity IgE receptor on lung dendritic cells during viral infection leads to mucous cell metaplasia. J Exp Med. 2007; 204:2759-69.
  • [23]Busse WW, Lemanske RF, Gern JE. The role of viral respiratory infections in asthma and asthma exacerbations. Lancet. 2010; 376:826-34.
  • [24]Jackson DJ, Sykes A, Mallia P, Johnston SL. Asthma exacerbations: origin, effect, and prevention. J Allergy Clin Immunol. 2011; 128:1165-74.
  • [25]Tam JS, Grayson MH. Dendritic cells, viruses, and the development of atopic disease. J Allergy. 2012;2012: Article ID 936870.
  • [26]Wegmann M. Targeting eosinophil biology in asthma therapy. Am Resp Cell Mol Biol. 2011; 45:667-74.
  • [27]Neighbour H, Boulet L-P, Lemiere C, Sehmi R, Leigh R, Sousa AR et al.. Safety and efficacy of an oral CCR3 antagonist in patients with asthma and eosinophilic bronchitis: a randomized, placebo-controlled clinical trial. Clin Exp Allergy. 2014; 44:508-16.
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