Oxidative Stress and Functional Lymphocyte Development

描述(申请人提供)：儿童哮喘患病率为 在工业化社会中急剧增加。这样做的原因是 不完全了解，虽然持续的室内空气变应原挑战， 接触工业污染物和烟草烟雾以及婴儿毛细支气管炎 都受到了牵连。从这些研究中，出现了哮喘的概念 是大多数累积风险因素发生在 关键序列，在发展的关键时刻。初级预防 消除或阻断这些风险中的任何一个都会导致哮喘。一 这种风险可能是氧化应激和抗氧化剂之间的平衡， 尤其是在肺部。最近的证据表明，氧化应激 可能影响小鼠T细胞反应的极化。的影响 氧化应激对人类Th2反应发展的影响尚不清楚，因为 是抗氧化剂的作用。该项目的具体目标是： 1.确定暴露在氧化和亚硝化应激下如何影响 各种抗原提呈细胞的功能。 2.检测氧化应激是否会改变T细胞的Th1/Th2平衡 对抗原的反应。 3.确定抗原提呈细胞的抗氧化剂治疗是否， 和/或T细胞，将改变T细胞对抗原的反应类型。 不同类型的抗原提呈细胞，包括单核细胞系和 原代细胞(如树突状细胞)将受到相关应激源的影响 并测试了它们调节共刺激蛋白表达的能力 分子、细胞因子和趋化因子。下生成的APC 然后将测试不同条件下的氧化应激的能力 支持或调节T细胞对Th1或Th2的极化反应。 最后，硫醇和非硫醇抗氧化剂调节 Th1或Th2反应的诱导将被确定。这些实验将 两者都回答了关于免疫反应发展的基本问题， 也为特定的临床试验提供了一个合理的框架 在关键时刻使用的抗氧化剂，主要用于预防哮喘。

DESCRIPTION (provided by applicant): The prevalence of childhood asthma is increasing dramatically in industrialized societies. The reasons for this are not completely understood, although persistent indoor aeroallergen challenge, exposure to industrial pollutants and tobacco smoke, and infant bronchiolitis have all been implicated. From these studies, the concept emerges that asthma is the result of a preponderance of accumulated risk factors occurring in a critical sequence, at a critical time in development. Primary prevention of asthma will result from elimination or interruption of any of these risks. One such risk may be the balance between oxidative stress and antioxidants, particularly in the lung. Recent evidence has suggested that oxidative stress may influence the polarization of T cell responses in mice. The effects of oxidative stress on the development of Th2 responses in humans are unknown, as are the effects of antioxidants. The Specific Aims of this Project are: 1. To determine how exposure to oxidative and nitrosative stress affects the function of various antigen presenting cells. 2. To test whether oxidative stress alters the Th1/Th2 balance of a T cell response to antigen. 3. To determine whether antioxidant treatment of antigen presenting cells, and/or T cells, will alter the type of T cell response to antigen. Different types of antigen presenting cells, including monocytic cell lines and primary cells (e.g., dendritic cells) will be subjected to relevant stressors and tested for their ability to modulate the expression of co-stimulatory molecules, cytokines, and chemokines. The APC that are generated under different conditions of oxidative stress will then be tested for the ability to support or modulate the polarization of T cell responses to Th1 or Th2. Finally, the ability of thiol and non-thiol antioxidants to modulate the induction of Th1 or Th2 responses will be determined. These experiments will both answer fundamental questions about the development of immune responses, but also provide a framework for rational clinical trials of specific antioxidants used at critical times for the primary prevention of asthma.