Regulation of Innate and Adaptive Immunity in Human COPD and Emphysema

描述（由申请人提供）： 与吸烟有关的肺部疾病是退伍军人残疾和死亡的最常见原因之一。尽管美国的吸烟率总体下降，但与普通人群中相同年龄组相比，退伍军人的吸烟率仍然较高。根据全国范围内的估计，美国超过75%的退伍军人是当前或以前的吸烟者，这使得这一群体患慢性阻塞性肺疾病（COPD）和肺气肿的风险非常高。COPD的特征是肺基质，特别是弹性蛋白的破坏，导致弹性回缩丧失、空气滞留和肺过度充气。除了巨噬细胞和嗜中性粒细胞之外，在患有肺气肿的受试者中检查的肺组织富含T辅助1型（Th 1）细胞、分泌细胞因子如白介素2（IL-2）和干扰素γ（IFN-g）的CD 4+和CD 8 + T淋巴细胞。我们发现，从肺气肿肺中分离的自身反应性淋巴细胞表达IFN-3诱导的10 kD蛋白（IP-10，CXCL 10），并强烈上调巨噬细胞弹性蛋白酶，特别是MMP 12和MMP 9。尽管这些数据表明人类COPD/肺气肿的适应性免疫基础，但我们对免疫应答如何启动和组织以对抗有毒吸入物（如烟草烟雾）知之甚少。此外，如在许多患有COPD的受试者中观察到的进行性肺破坏，甚至在戒烟后数年，表明存在独特的持久性抗原或免疫应答调节剂，其性质仍然完全不确定，但其促进适应不良的炎症应答。我们的两个具体目标是：目标1。探讨CD 4辅助性T细胞亚群在COPD和肺气肿发病机制中对基质金属蛋白酶的调节作用。为了支持这一目标，我们发现，尽管戒烟多年，Th 1细胞仍然存在于患有肺气肿的前吸烟者的肺中。目标2.确定补体蛋白在人肺气肿/COPD先天免疫和适应性免疫激活中的作用。为了支持这一目的，我们发现在肺气肿肺沉积大量的补体蛋白3（C3; C3 b，C3 d）的活化片段。对退伍军人医疗保健的潜在影响：我们提出的研究的成功将为COPD和肺气肿的机制提供新的理解，这将使该领域转向使用新型免疫药物的治疗。由于吸烟相关的肺部疾病在退伍军人中相当普遍，我们基于免疫的研究着眼于寻找可用于治疗肺气肿的新免疫调节剂，这将使这一人群受益匪浅。 公共卫生相关性： 本提案的目的是研究与人类肺气肿相关的白色血细胞类型，以制定治疗计划来阻止疾病的进展。我们相信，通过分离控制特殊白色血细胞分泌破坏性蛋白质的因素，我们可以找到阻止肺气肿进展的药物。这是一个令人兴奋的研究领域，可以使占一般吸烟人口很大一部分的退伍军人受益。

DESCRIPTION (provided by applicant): Cigarette smoke-related lung diseases is one of the most common causes of disability and death among veterans. Despite an overall decline in the smoking prevalence in the United States, smoking incidence remains higher in veterans when compared to the same age group in the general population. According to nationwide estimates, over 75% of the veterans in the United States are either current or former smokers which puts this group at a very high risk for developing chronic obstructive pulmonary disease (COPD) and emphysema. COPD is characterized by destruction of lung matrix, especially elastin, resulting in loss of elastic recoil, air trapping and lung hyperinflation. In addition to macrophages and neutrophils, lung tissue examined in subjects with emphysema is enriched with T helper type 1 (Th1) cells, CD4+ and CD8+ T lymphocytes that secrete cytokines such as interleukin 2 (IL-2), and interferon gamma (IFN-g). We found that autoreactive lymphocytes isolated from emphysematous lung express IFN-3 inducible protein of 10 kD (IP-10, CXCL10), and strongly up-regulate macrophage elastolytic proteinases, in particular MMP12 and MMP9. Although these data suggest an adaptive immune basis to human COPD/emphysema, we yet know little about how the immune response is initiated and organized against a toxic inhalant such as tobacco smoke. Further, progressive lung destruction as is observed in many subjects with COPD, even years after smoking cessation, suggests the presence of a uniquely persistent antigen or immune response modifier, the nature of which remains entirely undefined, but which promotes maladaptive inflammatory responses. Our two specific objectives are: Objective 1. To determine the role of CD4 T helper subsets in the regulation of MMPs in the pathogenesis of COPD and emphysema. In support of this aim, we have found that Th1 cells persist in the lung of former-smokers with emphysema despite years of smoking cessation. Objective 2. To determine the role of complement proteins in the activation of innate and adaptive immunity in human emphysema/COPD. In support of this aim, we have found in emphysematous lung deposition of large amounts of activated fragments of complement protein 3 (C3; C3b, C3d). Potential Impact on Veteran's Health Care: The success of our proposed studies will provide new understanding behind the mechanism of COPD and emphysema that will move the field towards therapies using novel immune-based medicines. Because smoking related lung diseases are quite prevalent among Veterans, our immune-based studies with an eye towards finding new immune modulators that could be used for treatment of emphysema will uniquely benefit this population. PUBLIC HEALTH RELEVANCE: The objective of this proposal is to investigate the type of white blood cells that are associated with human emphysema in order to develop a treatment plan to stop the progression of the disease. We believe that by isolating the factors that control the secretion of destructive proteins by special white blood cells, we could find drugs that would prevent the progression of emphysema. This is an exciting area of research that could benefit the veterans that make a large portion of the general smoking population.