TY - JOUR T1 - Blockade of Th1 chemokine receptors ameliorates pulmonary granulomatosis in mice JF - European Respiratory Journal JO - Eur Respir J DO - 10.1183/09031936.00070610 SP - erj00706-2010 AU - J. Kishi AU - Y. Nishioka AU - T. Kuwahara AU - S. Kakiuchi AU - M. Azuma AU - Y. Aono AU - H. Makino AU - K. Kinoshita AU - M. Kishi AU - R. Batmunkh AU - H. Uehara AU - K. Izumi AU - S. Sone Y1 - 2011/01/01 UR - http://erj.ersjournals.com/content/early/2011/01/27/09031936.00070610.abstract N2 - Sarcoidosis is a granulomatous disease of unknown cause. We identified immunological targets for the treatment of pulmonary granulomatosis using a murine model generated with Propionibacterium acnes (P. acnes).Sensitization and challenge using heat-killed P. acnes and dendritic cells (DCs) were performed to produce pulmonary granulomatosis in C57BL/6 mice. Immunological analyses using the ELISA as well as a cDNA microarray were used to search for cytokines or chemokines associated with the formation of granuloma 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 up-regulated during the granulomatosis. ELISA confirmed that levels of CXCL9 and CXCL10 as well as Th1 cytokines and chemokines including TNF-α and IFN-γ were elevated in BALF. The blockade of Th1 chemokine receptors using TAK-779, a dual blocker for CXCR3 and CCR5, demonstrated reduced numbers of CXCR3+CD4+ and CCR5+CD4+ T cells in BALF. Furthermore, the administration of TAK-779 ameliorated the granulomatosis.The targeted inhibition of Th1 chemokines might be useful for inhibiting Th1-biased granulomatous diseases including sarcoidosis. ER -