title: Blockade of Th1 chemokine receptors ameliorates pulmonary granulomatosis in mice.
abstract: Sarcoidosis is a granulomatous disease of unknown aetiology. We identified immunological targets for the treatment of pulmonary granulomatosis using a murine model generated with Propionibacterium acnes. Sensitisation and challenge using heat-killed P. acnes and dendritic cells (DCs) were performed to produce pulmonary granulomatosis in C57BL/6 mice. Immunological analyses using ELISA as well as cDNA microarray analysis were used to search for cytokines or chemokines associated with the formation of granulomas in the lungs. Co-administration of P. acnes and DCs reproducibly induced the formation of pulmonary granulomas, which resembled sarcoid granulomas. The cDNA microarray assay demonstrated that the gene expression of CXCL9 and CXCL10, ligands for CXCR3, and of CCL4, a ligand for CCR5, was strongly upregulated during granulomatosis. ELISA confirmed that levels of CXCL9 and CXCL10 as well as T-helper (Th)1 cytokines and chemokines including tumour necrosis factor-α and interferon-γ were elevated in bronchoalveolar lavage fluid (BALF). The blockade of Th1 chemokine receptors using TAK-779, a dual blocker for CXCR3 and CCR5, led to reduced numbers of CXCR3+CD4+ and CCR5+CD4+ T-cells in BALF. Furthermore, administration of TAK-779 ameliorated the granulomatosis. The targeted inhibition of Th1 chemokines might be useful for inhibiting Th1-biased granulomatous diseases, including sarcoidosis.
authors.affiliation: Department of Respiratory Medicine and Rheumatology, University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Kishi
authors.forename: Y
authors.initials: Y
authors.lastname: Nishioka
authors.forename: T
authors.initials: T
authors.lastname: Kuwahara
authors.forename: S
authors.initials: S
authors.lastname: Kakiuchi
authors.forename: M
authors.initials: M
authors.lastname: Azuma
authors.forename: Y
authors.initials: Y
authors.lastname: Aono
authors.forename: H
authors.initials: H
authors.lastname: Makino
authors.forename: K
authors.initials: K
authors.lastname: Kinoshita
authors.forename: M
authors.initials: M
authors.lastname: Kishi
authors.forename: R
authors.initials: R
authors.lastname: Batmunkh
authors.forename: H
authors.initials: H
authors.lastname: Uehara
authors.forename: K
authors.initials: K
authors.lastname: Izumi
authors.forename: S
authors.initials: S
authors.lastname: Sone
mesh_terms: D000577:Amides / Q000494:pharmacology; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D054407:Chemokine CCL4 / Q000096:biosynthesis / Q000276:immunology; D054357:Chemokine CXCL10 / Q000096:biosynthesis / Q000276:immunology; D054370:Chemokine CXCL9 / Q000096:biosynthesis / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects / Q000276:immunology; D006099:Granuloma / Q000188:drug therapy* / Q000276:immunology; D007371:Interferon-gamma / Q000032:analysis; D008171:Lung Diseases / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D011425:Propionibacterium acnes / Q000276:immunology; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D054367:Receptors, CXCR3 / Q000096:biosynthesis / Q000276:immunology; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: D000577:Amides; D054407:Chemokine CCL4; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; C485433:Cxcl10 protein, mouse; C485969:Cxcl9 protein, mouse; C515188:Cxcr3 protein, mouse; D000644:Quaternary Ammonium Compounds; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; C119369:TAK 779