Antagonism of chemokine receptor CCR8 is ineffective in a primate model of asthma

• Published in: Thorax Vol. 68; no. 6; pp. 506 - 512
• Main Authors: Wang, Lin, Jenkins, Tracy J, Dai, Mingshi, Yin, Wei, Pulido, Jacqueline C, LaMantia-Martin, Elise, Hodge, Martin R, Ocain, Timothy, Kolbeck, Roland
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group Ltd and British Thoracic Society 01.06.2013; BMJ Publishing Group LTD
• Subjects: Airway management; Airway Resistance - physiology; Allergens; Allergic lung disease; Allergies; Animals; Antigens; Ascaris suum; Asthma; Asthma - immunology; Asthma - metabolism; Asthma - physiopathology; Biological Factors - administration & dosage; Biological Factors - pharmacokinetics; Bronchoalveolar Lavage Fluid - chemistry; Chemokine CCL1 - antagonists & inhibitors; Chemokine CCL1 - biosynthesis; Chemokine CCL1 - immunology; Chemokines; Cynomolgus; Cytokines; Disease Models, Animal; Eosinophil Biology; Female; Inflammation; Infusions, Intravenous; Lavage; Leukocytes; Lung - drug effects; Lung - physiopathology; Lung Compliance; Lymphocyte Biology; Macaca fascicularis; Male; Pathogenesis; Primates; Pulmonary eosinophilia; Receptors, CCR8 - antagonists & inhibitors; Receptors, CCR8 - biosynthesis; Receptors, CCR8 - immunology; Th2 Cells - immunology; Th2 Cells - metabolism; United States > US; California; Lymphocyte Biology; Allergic lung disease; Pulmonary eosinophilia; Asthma; Eosinophil Biology
• ISSN: 0040-6376; 1468-3296
• DOI: 10.1136/thoraxjnl-2012-203012

Background Expression of the T-cell-associated chemokine receptor CCR8 and its ligand CCL1 have been demonstrated to be elevated in patients with asthma. CCR8 deficiency or inhibition in models of allergic airway disease in mice resulted in conflicting data. Objective To investigate the effects of a selective small molecule CCR8 inhibitor (ML604086) in a primate model of asthma. Methods ML604086 and vehicle were administered by intravenous infusion to 12 cynomolgus monkeys during airway challenge with Ascaris suum. Samples were collected throughout the study to measure pharmacokinetics (PK) and systemic CCR8 inhibition, as well as inflammation, T helper 2 (Th2) cytokines and mucus in bronchoalveolar lavage (BAL). Airway resistance and compliance were measured before and after allergen challenge, and in response to increasing concentrations of methacholine. Results ML604086 inhibited CCL1 binding to CCR8 on circulating T-cells>98% throughout the duration of the study. However, CCR8 inhibition had no significant effect on allergen-induced BAL eosinophilia and the induction of the Th2 cytokines IL-4, IL-5, IL-13 and mucus levels in BAL. Changes in airway resistance and compliance induced by allergen provocation and increasing concentrations of methacholine were also not affected by ML604086. Conclusions These results clearly demonstrate a dispensable role for CCR8 in ameliorating allergic airway disease in atopic primates, and suggest that strategies other than CCR8 antagonism should be considered for the treatment of asthma.