Therapeutic potential of anti-IL-6 therapies for granulocytic airway inflammation in asthma.
Therapeutic potential of anti-IL-6 therapies for granulocytic airway inflammation in asthma.
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DOI：
10.1186/s13223-015-0081-1
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Jordana M
中科院分区：
文献类型：
--
作者：
Chu DK;Al-Garawi A;Llop-Guevara A;Pillai RA;Radford K;Shen P;Walker TD;Goncharova S;Calhoun WJ;Nair P;Jordana M
确定哮喘炎症的细胞和分子表型可以确定可能从靶向治疗中受益最大的患者群体。尽管IL-6水平升高和IL-6信号的多态性与哮喘的肺功能障碍有关，但IL-6水平升高是否与特定的细胞炎症表型有关，以及IL-6阻断如何影响这种炎症反应仍不清楚。哮喘急性发作患者根据其呼吸道炎症特征(正常细胞计数、嗜酸性粒细胞、中性粒细胞、混合粒细胞)、痰细胞因子谱和肺功能进行表型分析。在存在或不存在内源性IL-6的情况下，小鼠暴露于常见的过敏原--屋尘螨(HDM)。分析在这些条件下肺部炎症的强度和性质，以及促粒细胞细胞因子和趋化因子的水平。嗜酸性-中性粒细胞混合性支气管炎患者IL-6升高与FEV1降低相关。在小鼠中，过敏原暴露增加了肺IL-6，而IL-6是由树突状细胞和肺泡巨噬细胞产生的。IL-6信号的功能丧失(敲除或抗体介导的中和)抑制了嗜酸性粒细胞和中性粒细胞的增加，募集细胞因子/趋化因子和过敏原诱导的小鼠呼吸道炎症。我们使用人类和动物数据证明了多效性细胞性呼吸道炎症与IL-6的相关性。这些数据表明，哮喘的恶化，特别是嗜酸性支气管炎和中性粒细胞支气管炎的合并，可能对针对IL-6途径的治疗有反应，因此，为启动临床试验来评估这一点提供了合理的基础。
Determining the cellular and molecular phenotypes of inflammation in asthma can identify patient populations that may best benefit from targeted therapies. Although elevated IL-6 and polymorphisms in IL-6 signalling are associated with lung dysfunction in asthma, it remains unknown if elevated IL-6 levels are associated with a specific cellular inflammatory phenotype, and how IL-6 blockade might impact such inflammatory responses. Patients undergoing exacerbations of asthma were phenotyped according to their airway inflammatory characteristics (normal cell count, eosinophilic, neutrophilic, mixed granulocytic), sputum cytokine profiles, and lung function. Mice were exposed to the common allergen, house dust-mite (HDM), in the presence or absence of endogenous IL-6. The intensity and nature of lung inflammation, and levels of pro-granulocytic cytokines and chemokines under these conditions were analyzed. Elevated IL-6 was associated with a lower FEV1 in patients with mixed eosinophilic-neutrophilic bronchitis. In mice, allergen exposure increased lung IL-6 and IL-6 was produced by dendritic cells and alveolar macrophages. Loss-of-function of IL-6 signalling (knockout or antibody-mediated neutralization) abrogated elevations of eosinophil and neutrophil recruiting cytokines/chemokines and allergen-induced airway inflammation in mice. We demonstrate the association of pleiotropic cellular airway inflammation with IL-6 using human and animal data. These data suggest that exacerbations of asthma, particularly those with a combined eosinophilic and neutrophilic bronchitis, may respond to therapies targeting the IL-6 pathway and therefore, provide a rational basis for initiation of clinical trials to evaluate this.
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影响因子：
168.9
作者：
Ferreira, Manuel A. R.;Matheson, Melanie C.;Duffy, David L.;Marks, Guy B.;Hui, Jennie;Le Souef, Peter;Danoy, Patrick;Baltic, Svetlana;Nyholt, Dale R.;Jenkins, Mark;Hayden, Catherine;Willemsen, Gonneke;Ang, Wei;Kuokkanen, Mikko;Beilby, John;Cheah, Faang;de Geus, Eco J. C.;Ramasamy, Adaikalavan;Vedantam, Sailaja;Salomaa, Veikko;Madden, Pamela A.;Heath, Andrew C.;Hopper, John L.;Visscher, Peter M.;Musk, Bill;Leeder, Stephen R.;Jarvelin, Marjo-Riitta;Pennell, Craig;Boomsma, Dorret I.;Hirschhorn, Joel N.;Walters, Haydn;Martin, Nicholas G.;James, Alan;Jones, Graham;Abramson, Michael J.;Robertson, Colin F.;Dharmage, Shyamali C.;Brown, Matthew A.;Montgomery, Grant W.;Thompson, Philip J.
通讯作者：
Thompson, Philip J.
DOI：
10.4049/jimmunol.0802923
发表时间：
2009-08-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Neveu WA;Allard JB;Dienz O;Wargo MJ;Ciliberto G;Whittaker LA;Rincon M
通讯作者：
Rincon M
影响因子：
4.4
作者：
Al-Garawi, Amal A.;Fattouh, Ramzi;Jordana, Manel
通讯作者：
Jordana, Manel
影响因子：
5.7
作者：
Nair, Parameswaran;Dasgupta, Angira;Chung, Kian Fan
通讯作者：
Chung, Kian Fan
DOI：
10.1016/j.jaci.2012.03.018
发表时间：
2012-08
期刊：
The Journal of allergy and clinical immunology
影响因子：
--
作者：
Hawkins GA;Robinson MB;Hastie AT;Li X;Li H;Moore WC;Howard TD;Busse WW;Erzurum SC;Wenzel SE;Peters SP;Meyers DA;Bleecker ER;National Heart, Lung, and Blood Institute–sponsored Severe Asthma Research Program (SARP)
通讯作者：
National Heart, Lung, and Blood Institute–sponsored Severe Asthma Research Program (SARP)