OX40L Interactions with Innate Immunity

OX40L 与先天免疫的相互作用

• 批准号: 7195678
• 负责人: Patricia W Finn
• 金额: $ 3.68万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7195678
• 关键词: T lymphocyte; asthma; binding proteins; cell population study; cytokine; dendritic cells; differentiation antigens; disease /disorder etiology; immune response; immunologic receptors; inflammation; laboratory mouse; lipopolysaccharides; nuclear factor kappa beta; pathologic process; respiratory hypersensitivity; toll like receptor

Asthma is a chronic inflammatory process mediated by aberrant adaptive (antigen dependent) and innate immune responses. Epidemiological studies have shown a correlation between exposure to endotoxin (LPS) during the first year of life and a lower prevalence of asthma. Experimental evidence supporting the notion that LPS responses affect asthma comes from our Preliminary Studies, which demonstrate that the LPS receptor TLR4 (Toll-like-receptor 4) regulates allergic responses in an established murine model of allergic asthma. Mice deficient in the key-adapter protein MyD88, critical for TLR4 signal transduction, have dramatically increased allergic responses. The data support our major postulate that the TLR4/MyD88 pathway plays a key-role in the suppression of allergic responses. Further support for this hypothesis comes from our observations that NF-kappaB which is activated by the TLR4/MyD88 signaling pathway, is crucial for pulmonary allergic inflammation. Our goal is to determine the mechanisms involved in TLR-4 mediated suppression of allergic responses. The fundamental strategy is to examine the contribution of the key molcules, TLR4, MyD88 and NF-kappaB in the modulation of allergic immune reponses. In Aims 1 and 2 we will examine how TLR4 signaling in T lymphocyte subsets and dendritic cells is critical for the pathogenesis of asthma. In our analysis of T cells, we will also determine whether CD4+CD25 + T regulatory (T regs) cells are critical regulators of allergic responses. In Aim 3, we propose to investigate the role of NF-kappaB genes in the modulation of allergic responses. The studies are designed to test our overall hypothesis that engagement of TLR-4 under defined conditions decreases allergic responses. Together, these experiments propose to clarify the interplay between innate and adaptive immunity in the development of pulmonary allergic inflammation, which may suggest therapeutic strategies applicable to allergy or asthma.

哮喘是一种由异常的适应性（抗原依赖性）和先天性免疫应答介导的慢性炎症过程。流行病学研究表明，在生命的第一年内暴露于内毒素（LPS）与哮喘发病率较低之间存在相关性。 支持LPS反应影响哮喘这一观点的实验证据来自我们的研究。 初步研究表明，LPS受体TLR 4（Toll样受体4）在已建立的过敏性哮喘小鼠模型中调节过敏反应。缺乏关键衔接蛋白MyD 88（对TLR 4信号转导至关重要）的小鼠过敏反应显著增加。这些数据支持我们的主要假设，即TLR 4/MyD 88通路在抑制过敏反应中起关键作用。对这一假设的进一步支持来自我们的观察，即由TLR 4/MyD 88信号通路激活的NF-κ B对肺部过敏性炎症至关重要。我们的目标是确定TLR-4介导的抑制过敏反应的机制。其基本策略是研究关键分子TLR 4、MyD 88和NF-κ B在过敏性免疫反应调节中的作用。在目标1和2中，我们将研究T淋巴细胞亚群和树突状细胞中的TLR 4信号传导如何在哮喘发病机制中起关键作用。在我们对T细胞的分析中， 还将确定CD 4 + CD 25 + T调节（T细胞）是否是过敏反应的关键调节因子。在目的3中，我们提出研究NF-κ B基因在过敏反应的调制中的作用。这些研究旨在测试我们的总体假设，即在限定条件下TLR-4的参与会降低过敏反应。总之，这些实验旨在阐明先天免疫和适应性免疫在肺部过敏性炎症发展中的相互作用，这可能表明适用于过敏或哮喘的治疗策略。