Distinct molecular endotypes in CD8+ T cells contribute to the pathogenesis of patients with the combination of COPD and asthma.

CD8 T 细胞中独特的分子内型有助于 COPD 和哮喘合并患者的发病机制。

• 批准号: 425340650
• 负责人: Professorin Dr. Michaela Schedel-Bockholt, Ph.D.
• 金额: --
• 依托单位: Klinik für Pneumologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/425340650?language=en
• 关键词: Distinct; molecular; endotypes; CD8+; cells

Chronic obstructive pulmonary disease (COPD), most often tobacco smoke-related, is characterized by a progressive loss of lung function, significant disability, and mortality. However, given the heterogeneity among patients, additional risk and genetic factors contribute to the decline in pulmonary function. A significant subset of patients have features of both COPD and asthma. Outcomes, including health-related quality of life impairment, are worse for patients with concomitant COPD and asthma compared to individuals with COPD alone. Presently, little information is available defining mechanisms accounting for more severe disease and treatment refractoriness in patients with COPD and asthma. Central to our hypothesis is that a subset of T lymphocytes, CD8+ T cells, are major contributors to more severe disease. In severe steroid-resistant asthmatics as well as in mouse models, we characterized an important role for CD8+ T cells capable of IL-13 production in an atopic (IL-4) environment with distinct cellular and molecular signatures. CD8+ T cells, unlike CD4+ T cells, are steroid-insensitive. Moreover, CD8+ T cells have been implicated in COPD because of their predominance in lung tissue. Similar to steroid-resistant asthmatics, CD8+ T cell numbers in the lung parenchyma and small airways inversely correlated with lung function and asthma-associated inflammatory pathways (type 2, IL-13) have been shown to contribute to the disease pathogenesis.Substantial interest exists to explore cellular and molecular mechanisms (endoytpes) that can be associated with different COPD phenotypes including COPD patients with co-existing asthma. The current proposal addresses this significant but unmet need to understand the consequences of COPD and asthma in the same patient using a candidate approach coupled with an untargeted approach. Analyzing the cellular and molecular programming of peripheral blood CD8+ T cells from COPD patients with or without asthma will elucidate, for the first time, distinct disease-causing pathways between subsets of COPD patients. COPD is not a uniform disease but with this approach novel identifiers to distinguish and classify different subsets of COPD patients will be developed. We will further elucidate how smoke exposure in COPD patients with or without asthma shifts networks and pathways leading to pathogenic CD8+ T cells. An important corollary to this work is the potential to identify a subset of patients who may benefit from Vitamin D treatment and the novel IL-4/IL-13 dual receptor antagonist, dupilumab. As an extension, we will be able to discover new target genes specific to patients with a concomitant diagnosis of COPD and asthma. Achieving these milestones will allow us to progress towards personalized medicine and to improve clinical practice in patients with chronic respiratory diseases.

慢性阻塞性肺疾病（COPD），最常见的与烟草烟雾有关，其特征在于肺功能的进行性丧失、严重残疾和死亡。然而，鉴于患者之间的异质性，其他风险和遗传因素导致肺功能下降。相当一部分患者同时具有COPD和哮喘的特征。与单纯COPD患者相比，COPD合并哮喘患者的结局（包括健康相关的生活质量损害）更差。目前，几乎没有信息可以定义COPD和哮喘患者更严重疾病和治疗难治性的机制。我们假设的核心是T淋巴细胞的一个亚群，CD 8 + T细胞，是更严重疾病的主要贡献者。在严重的类固醇抵抗性哮喘患者以及小鼠模型中，我们表征了能够在具有不同细胞和分子特征的特应性（IL-4）环境中产生IL-13的CD 8 + T细胞的重要作用。与CD 4 + T细胞不同，CD 8 + T细胞对类固醇不敏感。此外，CD 8 + T细胞由于其在肺组织中占优势而与COPD有关。与激素抵抗型哮喘相似，肺实质和小气道中的CD 8 + T细胞数量与肺功能和哮喘相关的炎症通路（2型，IL-13）呈负相关，已被证明有助于疾病的发病机制。目前的提案解决了这一重要但未满足的需求，即使用候选方法结合非靶向方法了解同一患者的COPD和哮喘的后果。分析COPD伴或不伴哮喘患者外周血CD 8 + T细胞的细胞和分子编程将首次阐明COPD患者亚群之间不同的致病途径。COPD不是一种统一的疾病，但通过这种方法，将开发用于区分和分类COPD患者不同子集的新标识符。我们将进一步阐明COPD患者的烟雾暴露如何改变导致致病性CD 8 + T细胞的网络和途径。这项工作的一个重要推论是，有可能确定一部分患者可能从维生素D治疗和新型IL-4/IL-13双重受体拮抗剂dupilumab中获益。作为扩展，我们将能够发现新的靶基因特异性的患者与COPD和哮喘的伴随诊断。实现这些里程碑将使我们能够朝着个性化医疗的方向发展，并改善慢性呼吸道疾病患者的临床实践。