OX40L Interactions with Innate Immunity

哮喘是由异常的适应性(抗原依赖性)和先天免疫反应介导的慢性炎症过程。流行病学研究表明，出生第一年暴露于内毒素(LPS)与较低的哮喘患病率之间存在相关性。 支持内毒素反应影响哮喘的实验证据来自我们的 初步研究表明，在已建立的过敏性哮喘小鼠模型中，脂多糖受体TLR4(Toll样受体4)调节过敏反应。缺乏对TLR4信号转导至关重要的关键适配蛋白MyD88的小鼠，显著增加了过敏反应。这些数据支持我们的主要假设，即TLR4/MyD88通路在抑制过敏反应中发挥关键作用。进一步支持这一假说的是我们的观察，即由TLR4/MyD88信号通路激活的NF-kappaB在肺变态反应性炎症中起着至关重要的作用。我们的目标是确定TLR-4介导的过敏反应抑制的机制。基本策略是研究关键分子TLR4、MyD88和NF-kappaB在调节变态反应免疫反应中的作用。在目标1和目标2中，我们将研究T淋巴细胞亚群和树突状细胞中的TLR4信号如何在哮喘发病机制中起关键作用。在我们的T细胞分析中，我们 也将确定CD4+CD25+T调节(T Regs)细胞是否是过敏反应的关键调节细胞。在目标3中，我们建议研究核因子-kappaB基因在变态反应调节中的作用。这些研究旨在测试我们的总体假设，即在特定条件下接触TLR-4可减少过敏反应。总之，这些实验建议阐明先天免疫和获得性免疫在肺变态反应性炎症发展过程中的相互作用，这可能会提出适用于过敏或哮喘的治疗策略。

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.