Phenotype and function of innate lymphoid cells in cystic fibrosis lung disease

囊性纤维化肺病中先天淋巴细胞的表型和功能

• 批准号: 428163432
• 负责人: Professorin Dr. Anna-Maria Dittrich
• 金额: --
• 依托单位: Klinik für Pädiatrische Pneumologie, Allergologie und Neonatologie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/428163432?language=en
• 关键词: Phenotype; function; innate; lymphoid; cells

Cystic fibrosis (CF) is the most common autosomal recessive progressive lung disease in Northern and Central Europe. CF lung disease is characterized by a vicious cycle of inflammation and infection that leads to progressive destruction of lung tissue. This destruction of lung tissue by a neutrophilic inflammation determines the course of the disease and still shortens the life expectancy of patients with cystic fibrosis. Anti-inflammatory approaches are therefore a central concern of patient-oriented CF research, especially as well-known anti-inflammatory drugs, such as steroids, have so far failed to show sufficient anti-inflammatory effects on CF lung disease.ILCs contribute to the early immune defense of a variety of bacterial and fungal infections characteristic of the acute and chronic respiratory tract infections in CF lung disease, e.g. Pseudomonas aeruginosa or Aspergillus fumigatus. As tissue-resident lymphocytes located beneath the mucosal surface, innate lymphoid cells (ILCs) respond to epithelial signals that control the expansion and differentiation of ILCs. ILCs in turn contribute to immune defense mechanisms by controlling the expansion and differentiation of other effector cells of the immune system and possibly support the formation of immunological memory. ILCs mediate these effects by cytokine secretion and surface molecules, such as costimulatory molecules, MHCII and checkpoint inhibitor molecules. Our preliminary data in CF lung tissue and CF-like mouse models suggest that ILCs contribute to the development of neutrophilic inflammation in CF lung disease. However, it has not yet been clarified which ILC-derived signals underlie neutrophilic lung inflammation in CF lung disease. Furthermore, the role of infectious and/or allergic stimuli for the contribution of ILCs to CF lung disease has not been addressed.The dependence of ILC effector function on secreted cytokines and surface molecules suggests that appropriate approaches to modulate ILC-associated cytokines and / or surface molecules may be a promising approach to target the neutrophil inflammatory response to influence CF lung disease. For this proposal, we therefore aim to identify ILC-associated mediators of CF lung disease by a comprehensive characterization of the repertoire of cytokines and surface molecules and other signaling pathways of CF lung tissue and CF-like mouse models. In a second step, we propose to assess the functional relevance of these mediators in appropriate mouse models and cell culture systems in order to provide a basis for further pre-clinical and clinical studies aimed at modulating the ILC-mediated inflammatory response in CF lung disease.

囊性纤维化（CF）是北方和中欧最常见的常染色体隐性进行性肺病。CF肺病的特征在于炎症和感染的恶性循环，其导致肺组织的进行性破坏。这种由嗜酸性炎症引起的肺组织破坏决定了疾病的进程，并且仍然缩短了囊性纤维化患者的预期寿命。因此，抗炎方法是面向患者的CF研究的中心关注点，特别是众所周知的抗炎药物，如类固醇，迄今为止未能对CF肺病显示出足够的抗炎作用。ILC有助于CF肺病中急性和慢性呼吸道感染特征的各种细菌和真菌感染的早期免疫防御，例如铜绿假单胞菌或烟曲霉。作为位于粘膜表面下的组织驻留淋巴细胞，先天性淋巴样细胞（ILC）响应控制ILC的扩增和分化的上皮信号。ILC进而通过控制免疫系统的其他效应细胞的扩增和分化来促进免疫防御机制，并可能支持免疫记忆的形成。ILC通过细胞因子分泌和表面分子如共刺激分子、MHCII和检查点抑制剂分子介导这些作用。我们在CF肺组织和CF样小鼠模型中的初步数据表明，ILC有助于CF肺病中嗜酸性炎症的发展。然而，它还没有被澄清，ILC衍生的信号的基础上嗜酸性肺炎症CF肺病。此外，感染性和/或过敏性刺激对ILC对CF肺疾病的贡献的作用尚未得到解决。ILC效应器功能对分泌的细胞因子和表面分子的依赖性表明，调节ILC相关细胞因子和/或表面分子的适当方法可能是靶向中性粒细胞炎症反应以影响CF肺疾病的有希望的方法。因此，我们的目标是通过全面表征CF肺组织和CF样小鼠模型的细胞因子和表面分子以及其他信号传导途径来鉴定CF肺病的ILC相关介质。在第二步中，我们建议在适当的小鼠模型和细胞培养系统中评估这些介质的功能相关性，以便为旨在调节CF肺病中ILC介导的炎症反应的进一步临床前和临床研究提供基础。