Th1 and Th17 Mediators in Experimental Emphysema

描述(由申请人提供)：肺相关抗原提呈细胞(APC)检测到每一次呼吸进入远端空间的无数毒素。它们能否平息或煽动对污染物的急性感知的炎症，可能会产生重要的后果。特别是无效的APC功能会导致免疫耐受、慢性感染或癌症，而抗原的异常处理可以诱导自身免疫。我们已经证明，患有肺气肿的吸烟者的一种亚型存在自身免疫性炎症，其特征是存在弹性蛋白特异性辅助性T细胞1型(Th1)和Th17细胞。抗原特异性T细胞诱导肺组织分泌基质金属蛋白酶(MMP12)，抑制α1抗胰蛋白酶(A1AT)，从而释放中性粒细胞弹性蛋白酶的活性，从而裂解弹性蛋白，削弱肺实质。然而，通过吸烟导致Th1和Th17细胞激活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，这表明修饰基因和环境暴露共同发挥了联合作用。我们发现从肺气肿小鼠肺中分离的APC可以诱导炎性细胞因子，并将其转移到NA小鼠体内，引起肺气肿。肺APC的基因芯片分析和我们的其他初步数据表明，芳香烃受体(AhR)、骨桥蛋白(SPP1)和抗炎转录因子过氧化体增殖物激活受体γ(PPAR-？)之间存在调节关系。因此，我们假设烟草烟雾通过作用于肺APC的独特的先天和获得性免疫机制来诱导Th1和Th17细胞。我们建议使用临床前肺气肿模型来确定芳烃受体在APC诱导的肺气肿致病T细胞活化中的前哨作用，以及II)确定PPAR-β-骨桥蛋白在香烟烟雾依赖的APC成熟和致病Th1和Th17细胞分化中的作用。这项应用捕捉了烟雾诱导的炎症中的一些关键启动事件，并应用这些知识来探索肺气肿的新治疗选择。

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.