Blockade of Th1 chemokine receptors ameliorates pulmonary granulomatosis in mice
Blockade of Th1 chemokine receptors ameliorates pulmonary granulomatosis in mice
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DOI：
10.1183/09031936.00070610
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发表时间：
2011-08-01
影响因子：
24.3
通讯作者：
Sone, S.
中科院分区：
文献类型：
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作者：
Kishi, J.;Nishioka, Y.;Sone, S.
结节病是一种病因不明的肉芽肿性疾病。我们使用痤疮丙酸杆菌（Propionibacterium acnes）产生的小鼠模型确定了用于治疗肺肉芽肿病的免疫学靶点，使用热灭活的痤疮丙酸杆菌和树突状细胞（DCs）进行致敏和攻击以产生C57 BL/6小鼠肺肉芽肿病。采用ELISA和cDNA微阵列分析的免疫学分析被用来寻找与肺肉芽肿形成相关的细胞因子或趋化因子。痤疮丙酸杆菌和DC的共同给药可重复地诱导肺肉芽肿的形成，其类似于结节性肉芽肿。cDNA微阵列分析表明，在肉芽肿病期间，CXCR 3的配体CXCL 9和CXCL 10以及CCR 5的配体CCL 4的基因表达强烈上调。ELISA证实支气管肺泡灌洗液（BALF）中CXCL9和CXCL10以及辅助性T细胞（Th）1细胞因子和趋化因子（包括肿瘤坏死因子-α和干扰素-γ）水平升高。使用TAK-779（CXCR3和CCR 5的双重阻断剂）阻断Th1趋化因子受体导致BALF中CXCR3 + CD4+和CCR 5 + CD4 + T细胞数量减少。此外，TAK-779给药可改善肉芽肿病。靶向抑制Th1趋化因子可能有助于抑制Th1偏向性肉芽肿病，包括结节病。
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-a and interferon-gamma 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.