Regulation of Innate and Adaptive Immunity in Human COPD and Emphysema

描述(由申请人提供)： 与吸烟相关的肺部疾病是导致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上有所下降，但与普通人群中的同一年龄段相比，退伍军人的吸烟率仍然较高。根据全国范围的估计，超过75%的美国退伍军人要么是现在的吸烟者，要么是曾经的吸烟者，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。慢性阻塞性肺疾病的特征是肺基质，特别是弹性蛋白的破坏，导致弹性回弹丧失，空气滞留和肺过度充气。除巨噬细胞和中性粒细胞外，肺气肿患者的肺组织中还富含辅助性T细胞1型(Th1)、分泌白细胞介素2(IL-2)和干扰素-γ(干扰素-g)等细胞因子的CD4+和CD8+T淋巴细胞。我们发现，从肺气肿肺分离的自身反应性淋巴细胞表达10kD的干扰素-3诱导蛋白(IP-10，CXCL10)，并强烈上调巨噬细胞弹性蛋白酶，尤其是MMP12和MMP9。尽管这些数据表明人类COPD/肺气肿具有适应性免疫基础，但我们对免疫反应是如何启动和组织起来的，如烟草烟雾等有毒吸入剂知之甚少。此外，在许多COPD患者中观察到的进行性肺破坏，即使在戒烟多年后，也表明存在一种独特的持久性抗原或免疫反应调节剂，其性质仍未完全确定，但它促进了不适应的炎症反应。我们的两个具体目标是：目的1.确定CD4T辅助细胞亚群在调节MMPs在COPD和肺气肿发病机制中的作用。为了支持这一目标，我们发现，尽管戒烟多年，但患有肺气肿的前吸烟者的肺中仍存在Th1细胞。目的2.探讨补体蛋白在肺气肿/慢性阻塞性肺疾病先天免疫和获得性免疫激活中的作用。为了支持这一目标，我们发现在肺气肿肺中沉积了大量的补体蛋白3(C3；C3b，C3d)的活性片段。对退伍军人保健的潜在影响：我们建议的研究的成功将提供对COPD和肺气肿机制的新理解，这将推动该领域转向使用新型免疫药物的治疗。由于与吸烟相关的肺部疾病在退伍军人中相当普遍，我们以免疫为基础的研究着眼于寻找新的免疫调节剂，可用于治疗肺气肿，这将使这一群体独特受益。 公共卫生相关性： 这项建议的目的是调查与人类肺气肿有关的白细胞类型，以制定阻止疾病进展的治疗计划。我们相信，通过分离控制特殊白细胞分泌破坏性蛋白质的因素，我们可以找到阻止肺气肿恶化的药物。这是一个令人兴奋的研究领域，可能会让占普通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.