Th1 and Th17 Mediators in Experimental Emphysema

描述（由申请人提供）：肺相关抗原呈递细胞（APC）检测每次呼吸进入远端空气空间的无数毒素。它们在急性感受到污染物时是平息还是煽动炎症可能具有重要意义。特别是无效的APC功能导致免疫耐受、慢性感染或癌症，而抗原的异常加工可诱导自身免疫。我们已经证明，一个亚型的吸烟者谁发展肺气肿港口自身免疫性炎症，其特征是存在弹性蛋白特异性T辅助1型（Th 1）和Th 17细胞。抗原特异性T细胞诱导肺中的基质金属蛋白酶（MMP）12分泌，其抑制α 1抗胰蛋白酶（A1 AT），从而释放中性粒细胞弹性蛋白酶的活性，所述中性粒细胞弹性蛋白酶切割弹性蛋白并削弱肺实质。然而，通过香烟烟雾导致Th 1和Th 17细胞活化和肺气肿的免疫事件仍然不清楚。此外，即使在吸烟者中，也存在很大的表型变异性，表明修饰基因和环境暴露一起产生综合效应。我们已经发现，从肺气肿小鼠中分离的肺APC可以诱导炎性细胞因子，并在转移到幼稚小鼠时引起肺气肿。肺APC的基因微阵列分析和我们额外的初步数据表明，芳香烃受体（AhR）、骨桥蛋白（SPP 1）和过氧化物酶体增殖物激活受体γ（PPAR-γ）之间存在调节关系，抗炎转录因子。因此，我们假设烟草烟雾诱导Th 1和Th 17细胞通过独特的先天性和适应性免疫机制在肺APC中起作用。我们建议使用肺气肿的临床前模型，i）确定芳烃受体在肺气肿APC诱导的致病性T细胞活化中的哨兵作用，和ii）确定PPAR-？骨桥蛋白在香烟烟雾依赖性APC成熟和致病性Th 1和Th 17细胞分化中的作用。该应用程序捕获了吸烟引起的炎症中的一些关键起始事件，并将这些知识应用于探索肺气肿的新治疗方案。

DESCRIPTION (provided by applicant): Lung-associated antigen presenting cells (APCs) detect innumerable toxins that enter the distal airspaces with each breath. Whether they quell or incite inflammation upon acute sensing of pollutants could be of important consequence. Specifically ineffective APC function results in immune tolerance, chronic infections, or cancer, whereas aberrant processing of antigen can induce autoimmunity. We have demonstrated that a subtype of smokers who develop emphysema harbor autoimmune inflammation, characterized by the presence of elastin- specific T helper type 1 (Th1) and Th17 cells. Antigen specific T cells induce matrix metalloproteinase (MMP) 12 secretion in the lung that inhibits alpha 1 anti-trypsin (A1AT), thereby unleashing the activity of neutrophil elastase that cleaves elastin and weakens lung parenchyma. However, the immune events leading to the activation of Th1 and Th17 cells and emphysema through cigarette smoke remain obscure. Further, even among smokers, there exists large phenotypic variability suggesting that modifier genes and environmental exposures together exert a combined effect. We have found that lung APCs isolated from mice with emphysema can induce inflammatory cytokines, and cause emphysema when transferred to na¿ve mice. Gene microarray analysis of lung APCs and our additional preliminary data suggest the presence of a regulatory relationship between the aryl hydrocarbon receptor (AhR), osteopontin (SPP1), and peroxisome proliferator- activated receptor gamma (PPAR-?), an anti-inflammatory transcription factor. Therefore, we hypothesize that tobacco smoke induces Th1 and Th17 cells through unique innate and adaptive immune mechanisms operative in lung APCs. We propose using a preclinical model of emphysema to i) Determine the sentinel role of the aryl hydrocarbon receptor in APC-induced pathogenic T cell activation in emphysema, and to ii) Determine the role of PPAR-?-osteopontin in cigarette smoke-dependent APC maturation and pathogenic Th1 and Th17 cell differentiation. This application captures some of the critical initiation events in smoke-induced inflammation and applies this knowledge to explore new therapeutic options in emphysema.