Lauzon-Joset Jean-François, Langlois Anick, Lai Laetitia J A, Santerre Kim, Lee-Gosselin Audrey, Bossé Ynuk, Marsolais David, Bissonnette Elyse Y
Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Quebec City, Quebec; and Department of Medicine, Laval University, Quebec City, Quebec, Canada.
Am J Respir Cell Mol Biol. 2015 Aug;53(2):276-84. doi: 10.1165/rcmb.2014-0229OC.
In allergic asthma, homeostatic pathways are dysregulated, which leads to an immune response toward normally innocuous antigens. The CD200-CD200 receptor pathway is a central regulator of inflammation, and CD200 expression was recently found to be down-regulated in circulating leukocytes of patients with asthma. Given the antiinflammatory properties of CD200, we investigated whether local delivery of recombinant CD200 (rCD200) could reinstate lung homeostasis in an experimental model of asthma. Brown Norway rats were sensitized with ovalbumin (OVA) and alum. rCD200 was intratracheally administered 24 hours before OVA challenge, and airway responsiveness to methacholine was measured 24 hours after the allergen challenge. Inflammation was also assessed by measuring cell recruitment and cytokine levels in bronchoalveolar lavages, as well as lung and draining lymph node accumulation of dendritic cells (DCs) and T cells. In sensitized rats, rCD200 abolished airway hyperresponsiveness, whereas the sham treatment had no effect. In addition, rCD200 strongly reduced OVA-induced lung accumulation of myeloid DCs, CD4(+) T cells, and T helper type 2 cells. This was associated with a strong reduction of OVA-induced IL-13 level and with an increase of IL-10 in supernatants of bronchoalveolar lavages. Lung eosinophilia and draining lymph node accumulation of myeloid DCs and T cells were not affected by rCD200. Overall, these data reveal that rCD200 can inhibit airway hyperresponsiveness in a model of asthma by a multistep mechanism associated with local alterations of the T cell response and the cytokine milieu.
在过敏性哮喘中，稳态通路失调，导致对通常无害抗原产生免疫反应。CD200 - CD200受体通路是炎症的核心调节因子，最近发现哮喘患者循环白细胞中CD200表达下调。鉴于CD200的抗炎特性，我们研究了在哮喘实验模型中局部递送重组CD200（rCD200）是否能恢复肺内稳态。用卵清蛋白（OVA）和明矾对棕色挪威大鼠进行致敏。在OVA激发前24小时经气管内给予rCD200，并在变应原激发后24小时测量气道对乙酰甲胆碱的反应性。还通过测量支气管肺泡灌洗中的细胞募集和细胞因子水平，以及肺和引流淋巴结中树突状细胞（DCs）和T细胞的积聚来评估炎症。在致敏大鼠中，rCD200消除了气道高反应性，而假处理则无效果。此外，rCD200强烈减少了OVA诱导的髓样DCs、CD4(+) T细胞和2型辅助性T细胞在肺内的积聚。这与OVA诱导的IL - 13水平的强烈降低以及支气管肺泡灌洗上清液中IL - 10的增加有关。肺嗜酸性粒细胞增多以及髓样DCs和T细胞在引流淋巴结中的积聚不受rCD200影响。总体而言，这些数据表明rCD200可通过与T细胞反应和细胞因子环境的局部改变相关的多步骤机制抑制哮喘模型中的气道高反应性。
