Effect of intranasal exposure to cigarette smoke on the Immune System as a model for COPD

我们已经开展了广泛的研究，检查免疫系统在慢性阻塞性肺疾病（COPD）中的作用。慢性阻塞性肺病仍然是一种日益增长但被忽视的全球流行病。我们的研究利用了人类样本，在确定细胞毒性细胞、NK细胞、NKT细胞和B细胞在疾病中的重要作用方面发挥了关键作用。我们目前正在利用这些知识来鉴定可能用于治疗COPD的新化合物（MRC P2D资助）。目前，准确反映COPD表型的小鼠模型有限，而且在中部地区没有可用的模型。因此，这个博士项目的目标将是开发一个鼻内香烟烟雾模型，以便全面研究免疫系统，特别是研究已知与疾病相关的免疫系统细胞和介质。CD8+ t淋巴细胞、自然杀伤t样细胞（NKT）和自然杀伤细胞（NK）是参与COPD发病机制的人类杀伤细胞的三大类。我们已经证明，这些细胞在COPD患者外周血中的数量和细胞毒功能都有所减少（Urbanowicz et al ., 2009），但在COPD患者的肺部中，这些细胞的数量和细胞毒功能却相反上调（Urbanowicz et al ., 2010）。此外，这些细胞的激活可以通过产生炎症细胞因子和趋化因子引发免疫反应，导致肺组织损伤、粘液分泌过多和肺气肿。我们已经表明，系统激活似乎与当前吸烟有关，而肺部激活与是否存在COPD有关，而与当前吸烟状态无关（Wang等，2012）。这些发现表明，调节杀伤细胞功能和/或激活可能是治疗COPD的新靶点。此外，我们发现多种细胞因子在COPD中共同升高（Selvarajah等人，2016），特别是我们发现许多循环细胞因子升高，以至于它们的联合而不是个体的升高与疾病的严重程度显著相关，这些可能是COPD全身性炎症表现的进一步指标和因素。此外，我们还发现多种自身抗体（AAbs）在COPD中升高（Shindi et al, 2017）。有趣的是，COPD血清中IgM抗体与IgG抗体的自身抗原特异性存在显著差异：例如，针对组蛋白和scl-70的抗体主要是IgG抗体，而针对CENP-B和La/ssB的抗体主要是IgM抗体；相比之下，IgM和iggab对胶原- v同样普遍。因此，在所有COPD病例中检测到针对多种自身抗原的IgM和IgG抗体组合，而所有非COPD对照者的抗体均为阴性。这突出了不同类型的自身抗体在COPD中对一系列自身抗原的重要性。该项目将开发一个小鼠模型，以检查已知在导致COPD的生物学机制中重要的细胞、细胞因子和自身抗体的作用。

We have carried out extensive research examining the role of the immune system in Chronic Obstructive Pulmonary Disease (COPD). COPD remains a growing but neglected global epidemic. Our research utilised human samples and was key in identifying the important role for cytotoxic cells, NK cells, NKT cells and B cells in disease. We are currently using this knowledge to identify novel compounds that may be used for treatment of COPD (MRC P2D funding). Presently there are limited murine models that accurately reflect COPD phenotype and none are available in the Midlands. As such the aim of this PhD project will be to develop an intranasal cigarette smoke model to enable comprehensive study of the immune system, specifically with the goal of examining cells and mediators of the immune system known to be related to disease. CD8+ T-lymphocytes, natural killer T-like (NKT) cells and natural killer (NK) cells are the three main classes of human killer cells that are implicated in the pathogenesis of COPD. We have shown that these cells are reduced in both number and cytotoxic function in the peripheral blood of COPD patients (Urbanowicz et al, 2009), but conversely are up-regulated in number and cytotoxic function in the lungs of COPD patients (Urbanowicz et al, 2010). In addition, activation of these cells can initiate immune responses by virtue of their production of inflammatory cytokines and chemokines that cause lung tissue damage, mucus hypersecretion and emphysema. We have shown systemic activation appears to be related to current smoking whereas lung activation is related to the presence or absence of COPD, irrespective of current smoking status (Wang et al, 2012). These findings suggest that modulating killer cell function and/or activation may be a new target for the treatment of COPD. In addition, we have shown that multiple cytokines are co-elevated in COPD (Selvarajah et al, 2016), specifically we showed numerous circulating cytokines were raised such that their combined, but not individual, elevation was significantly associated with severity of disease, and these may be further indicators of, and contributors to, the systemic inflammatory manifestations of COPD. Furthermore, we have shown multiple autoantibodies (AAbs) are elevated in COPD (Shindi et al, 2017). Interestingly, there were significant differences in the autoantigenic specificities of IgM AAbs compared to IgG AAbs in the COPD sera: for example, AAbs to histone and scl-70 were mainly IgG, whereas AAbs to CENP-B and La/ssB were mainly IgM; by contrast, IgM and IgGAAbs to collagen-V were equally prevalent. Thus, a combination of IgM and IgG AAbs specific for multiple autoantigens are detected in all cases of COPD at a level at which all non-COPD controls are negative for AAbs. This highlights the importance of different classes of AAbs to a range of autoantigens in COPD. This project will develop a murine model to examine the role of cells, cytokines and autoantibodies known to be important in the biological mechanisms leading to COPD.