Ancillary T Cell Based Studies in SPIROMICS

描述（由申请人提供）：该辅助申请的长期目标是表征具有自身反应性T细胞反应的吸烟者亚群，验证可检测肺气肿的免疫诊断分析，并在参与SPROMICS （UCSF中心）的具有良好特征的队列中发现致病性T细胞发育的分子特征。我们面临的主要医学挑战之一是，吸烟引起的肺部疾病的易感性差异很大，这基本上使我们无法预测哪些吸烟者会患肺气肿。由于SPIROMICS研究旨在对一个庞大且异质性的吸烟者群体进行表型分析，我们选择了这个队列来确定具有自身反应性T细胞的亚群，因为这可能代表了肺气肿发展的一种促进机制，这可能需要替代疗法，并且可能代表了一组尽管戒烟仍将患有进行性疾病的患者。在Aim 1中，我们将前瞻性地确定自身反应性T细胞反应的存在，通过增加细胞因子释放来确定180例有肺气肿和无肺气肿的吸烟者；在目标2中，我们将重点关注可能在高危人群中易发自身反应性T细胞的因素的纵向方面。这些研究为开发新的基于免疫的人类肺气肿诊断和治疗策略奠定了基础。这里概述的短期目标是基于我们的初步数据，并提供了必要的平台，将用于回答以下紧迫问题：i)在一个独特的前瞻性队列吸烟者中，自身反应性T细胞能否预测影像学肺气肿的存在？ii)我们能否确定与自身免疫性肺气肿相关的独特和持续的转录特征？SPIROMICS的观察性和纵向设计允许对肺气肿作为主要临床终点之间的关联进行详细评估，并可以验证我们实验室开发的新型T细胞特异性免疫诊断潜力。我们建议探索自身免疫在肺气肿发展中的作用，并将当前技术应用于临床和未来的诊断测试。

DESCRIPTION (provided by applicant): The long-term objectives of this ancillary application are to characterize a subpopulation of smokers with auto-reactive T cell response, to validate immunodiagnostic assays that could detect emphysema, and to find molecular signatures for pathogenic T cell development in a well-characterized cohort participating in SPROMICS (UCSF center). One of the major medical challenges facing us is that susceptibility to smoking-induced lung diseases varies greatly and essentially precludes our ability to predict which smokers will develop emphysema. Because the SPIROMICS study is designed to phenotype a large and heterogeneous group of smokers, we have chosen this cohort to identify the subpopulation who have auto-reactive T cells, as this may represent a contributing mechanism in the development of emphysema, which may need alternative therapies, and may represent a group of patients who will have progressive disease despite smoking cessation. In Aim 1, we will prospectively determine the presence of auto-reactive T cell responses as determined by increased cytokine release in 180 ever-smokers with and without emphysema; in Aim 2 we will focus on the longitudinal aspect of the factors that could predispose development of auto-reactive T cells in the population at risk. These studies form the prerequisite basis for developing additional novel immune-based diagnostic and therapeutic strategies in human emphysema. The short-term objectives outlined here are based on our preliminary data, and provide the necessary platform that will be used to answer the following urgent questions: i) in a distinct prospective cohort of ever smokers, can auto-reactive T cells predict the presence of radiographic emphysema? ii) Can we identify unique and persistent transcriptional signature(s) that are associated with autoimmune emphysema? The observational and longitudinal design of SPIROMICS allows for detailed assessment of the association between emphysema as the primary clinical endpoints and could validate the novel T cell specific immunodiagnostic potential that has been developed in our laboratory. We propose to explore the role of autoimmunity as a contributing mechanism in the development of emphysema with the additional aim of bringing current technologies to bear on clinical and future diagnostic tests.