Ancillary T Cell Based Studies in SPIROMICS

描述(由申请人提供)：这一辅助申请的长期目标是确定具有自身反应性T细胞反应的吸烟者亚群的特征，验证可以检测肺气肿的免疫诊断分析，并在参与SPROMICS(加州大学旧金山分校中心)的特征良好的队列中寻找致病T细胞发展的分子特征。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，从本质上说，我们无法预测哪些吸烟者会患上肺气肿。由于SPIROMICS研究旨在对一大群不同类型的吸烟者进行表型，我们选择了这一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的发生机制，这可能需要替代疗法，并可能代表一组即使戒烟但仍将出现进展性疾病的患者。在目标1中，我们将前瞻性地确定180名患有肺气肿和不患有肺气肿的吸烟者中细胞因子释放增加所确定的自身反应性T细胞反应的存在；在目标2中，我们将重点放在可能导致高危人群中自身反应性T细胞发展的因素的纵向方面。这些研究形成了开发新的基于免疫的人类肺气肿诊断和治疗策略的先决条件基础。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，将被用来回答以下紧迫的问题：i)在一个不同的吸烟者预期队列中，自身反应性T细胞能否预测放射学肺气肿的存在？Ii)我们能否识别出与自身免疫性肺气肿相关的独特且持久的转录签名(S)？SPIROMICS的观察性和纵向设计允许详细评估作为主要临床终点的肺气肿之间的关联，并可以验证我们实验室开发的新的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机制，并将现有技术应用于临床和未来的诊断测试。公共卫生相关性：我们在吸烟者中发现了患有呼吸系统疾病的特异性自身反应性T细胞，而且越来越多的证据表明，这些特异性效应细胞与吸烟相关肺部疾病的病理生理学有关。我们建议的研究很重要，因为它们将为患有或有发展为肺气肿风险的吸烟者提供新的诊断和预后分析(例如，基于Th1和Th17细胞因子的-6-SPOT)。

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. PUBLIC HEALTH RELEVANCE: We have discovered specific autoreactive T cells in ever-smokers with emphsyema and there is growing evidence linking these particular effector cells with the pathophysiology of smoking related lung disease. Our proposed studies are important because they will provide new diagnostic and prognostic assays (e.g. ¿-6-Spot, based on Th1 and Th17 cytokines) in ever-smokers who have, or are at risk of developing emphysema.