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描述具有自身反应性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试验，并寻找致病性T细胞发育的分子特征在参与SPROMICS（加州大学旧金山分校中心）的特征良好的队列中。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，基本上排除了我们预测哪些吸烟者将发展为肺气肿的能力。由于SPIROMICS研究旨在对大量异质性吸烟者进行表型分析，因此我们选择该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生的一种促进机制，可能需要替代疗法，并且可能代表了一组尽管戒烟仍会发生疾病进展的患者。在目标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180例有或无肺气肿的吸烟者的细胞因子释放来确定;在目标2中，我们将重点关注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。这些研究形成了在人类肺气肿中开发其他新的基于免疫的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，将用于回答以下紧迫的问题：i）在一个独特的前瞻性队列的吸烟者，自身反应性T细胞可以预测放射性肺气肿的存在？ii）我们能否鉴定与自身免疫性肺气肿相关的独特且持久的转录特征？SPIROMICS的观察性和纵向设计允许详细评估肺气肿作为主要临床终点之间的相关性，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作为肺气肿发展中的一种促进机制的作用，并将当前的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.