Myeloid regulatory cells in allergic airway inflammation

过敏性气道炎症中的骨髓调节细胞

• 批准号: 7753950
• 负责人: Jessy Satyadas Deshane
• 金额: $ 5.19万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7753950
• 关键词: Address; Adoptive Transfer; Air; Allergens; Allergic; Anti-Asthmatic Agents; Antigens; Asthma; Attenuated; Biological Availability; Bronchoalveolar Lavage Fluid; Cells; Chronic; Data; Disease; Equilibrium; Exhalation; Free Radicals; Generations; Immune; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Lung; Mediating; Mission; Modeling; Mus; Myelogenous; Myeloid Cells; NADPH Oxidase; National Heart, Lung, and Blood Institute; Neutrophil Infiltration; Nitric Oxide; Ovalbumin; Pathway interactions; Population; Process; Public Health; Recruitment Activity; Research Proposals; Role; Severity of illness; Source; Structure of parenchyma of lung; Superoxides; T-Cell Proliferation; Testing; Tissues; airway hyperresponsiveness; airway inflammation; allergic airway inflammation; antigen challenge; arginase; asthmatic patient; cytokine; human NOS2A protein; in vivo; mouse model; novel; research study

DESCRIPTION (provided by applicant): Hypothesis: Myeloid derived regulatory cells (MDRC), recruited to the lung during allergic airway inflammatory responses such as asthma, help to control the level of tissue inflammation by regulating the bioavailability of reactive free radicals, including nitric oxide (NO) and superoxide (02-). Specific Aims: (1) To test the hypothesis that myeloid subpopulations recruited to the lung of sensitized mice following antigen challenge generate and regulate the critical balance of reactive free radicals during allergic airway inflammation (2) Determine whether MDRC attenuate the asthmatic inflammatory response by mechanisms using reactive free radical species in a mouse model. Experimental Approach: C57BL/6, INOS-/- or B6 (Cg)-Ncf1m1 J/J mice will be sensitized intraperitoneally and challenged with the intranasal antigen, ovalbumin (OVA). Bronchoalveolar lavage (BAL) fluid and lung tissue will be examined for (1) dynamics of recruitment of MDRC (2) function of MDRC including phagocytic ability, and generation of cytokines and free radical species by MDRC. In addition, we will investigate (3) whether MDRC mediate suppression of T cell proliferation in vitro via iNOS, Arginase or NADPH oxidase pathways (4) whether MDRC mediate suppression of T cell proliferation following adoptive transfer in vivo and the role of NO and 02- in this effect, and (5) whether the adoptively transferred MDRC modulate airway hyper-responsiveness in a model of airway inflammation. Rationale: During allergic airway inflammatory responses, innate cells are recruited to the lung prior to adaptive immune cells. We present preliminary data to show (1) that two subsets of MDRC which generate O2- and NO are recruited to the lungs, and (2) MDRC suppress T cell proliferation via mechanisms that depend on free radicals, suggesting the potential for these cells to attenuate inflammation in vivo. Relevance to Public Health and the NHLBI Mission: The proposed studies will test directly the potential of MDRC to suppress asthma disease severity, potentially identifying novel targets for anti-asthmatic therapy.

描述（由申请人提供）：假设：在过敏性气道炎症反应（如哮喘）期间招募至肺的髓源性调节细胞（MDRC）通过调节活性自由基（包括一氧化氮（NO）和超氧化物（O2-））的生物利用度来帮助控制组织炎症水平。具体目标：（1）验证抗原激发后募集到致敏小鼠肺中的髓系亚群在过敏性气道炎症期间产生并调节反应性自由基的临界平衡的假设。（2）确定MDRC是否通过小鼠模型中使用反应性自由基种类的机制减轻哮喘炎症反应。实验方法：C57 BL/6、INOS-/-或B6（Cg）-Ncf 1 m1 J/J小鼠将腹腔内致敏，并用鼻内抗原卵清蛋白（OVA）激发。将检查支气管肺泡灌洗液（BAL）和肺组织的（1）MDRC募集的动力学（2）MDRC的功能，包括吞噬能力，以及MDRC产生的细胞因子和自由基种类。此外，我们将研究（3）MDRC是否通过iNOS、精氨酸酶或NADPH氧化酶途径介导体外T细胞增殖的抑制，（4）MDRC是否介导体内过继转移后T细胞增殖的抑制以及NO和O2-在该效应中的作用，和（5）过继转移的MDRC是否调节气道炎症模型中的气道高反应性。原理：在过敏性气道炎症反应期间，先天性细胞在适应性免疫细胞之前被招募到肺中。我们提供的初步数据表明：（1）产生O2-和NO的MDRC的两个子集被招募到肺部，（2）MDRC通过依赖于自由基的机制抑制T细胞增殖，表明这些细胞有可能减轻体内炎症。与公共卫生和NHLBI使命的相关性：拟议的研究将直接测试MDRC抑制哮喘疾病严重程度的潜力，可能确定抗哮喘治疗的新靶点。