Molecular and Cellular Pathogenesis of Pulmonary Langerhans Cell Histiocytosis

肺朗格汉斯细胞组织细胞增多症的分子和细胞发病机制

• 批准号: 10658208
• 负责人: Michael Borchers
• 金额: $ 56.78万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658208
• 关键词: Address; Adoptive Transfer; BRAF gene; Benign; Biological; Biological Assay; Biopsy; Blocking Antibodies; CCL20 gene; CCL7 gene; Cell Aging; Cell Maturation; Cell Therapy; Cell surface; Cells; Chronic; Cigarette Smoker; Clinical Trials; Communities; Cyst; Cystic Lesion; Cytolysis; Data; Dendritic Cells; Development; Diagnosis; Disease; Eosinophilic Granuloma; Event; Exhibits; Exposure to; Generations; Goals; Homeostasis; Human; ITGAX gene; Immune Evasion; In Vitro; Induced Mutation; Inflammation; Inflammatory; Interstitial Lung Diseases; Knowledge; Lesion; Leukocytes; Life; Ligands; Link; Lung; Lung diseases; Lymphocyte; Lymphokine-Activated Killer Cells; MAPK Signaling Pathway Pathway; Mediating; Modeling; Molecular; Molecular Target; Morbidity - disease rate; Mus; Mutant Strains Mice; Mutation; Myelogenous; Nature; Neoplasms; Nodule; Pathogenesis; Pathology; Pathway interactions; Patients; Phosphotransferases; Pre-Clinical Model; Process; Production; Public Health; Reporting; Research; Role; Source; Specificity; Testing; Time; Up-Regulation; chemokine; cytokine; cytotoxic; cytotoxicity; effective therapy; evidence base; experimental study; exposure to cigarette smoke; histiocyte; immune function; insight; langerin; lung lesion; monocyte; mortality; mutant; novel; novel therapeutics; preclinical study; preservation; receptor; recruit; therapeutic target; therapy development

Project Summary. Pulmonary Langerhans Cell Histiocytosis (PLCH) is a rare interstitial lung disease, which occurs almost exclusively in cigarette smokers and has a median duration of survival from of of 12.5 years. PLCH is characterized by,Langerin+ dendritic cell (DC) accumulation, inflammatory lesions, nodule formation and cystic remodeling. Recently, a causative link between acquired BRAF (kinase in RAS pathway) mutations in the myeloid/monocyte lineage and the development of benign neoplasms has been reported, and a common, acquired mutation in BRAF (V600E) was found in lung lesions of more than half of PLCH patients. Although this causal link represents an important breakthrough, the mechanisms by which mutant histiocytes control the initiation and progression of PLCH are unknown. To address this critical knowledge gap, we have developed preclinical models that recapitulate hallmark features of PLCH. We show that cigarette smoke (CS) exposure of mice expressing an inducible BRAFV600E mutation in CD11c+ cells exhibit peribronchiolar inflammation, nodule formation, and airspace enlargement accompanied by cyst-like formations. These structural changes are accompanied by alterations in DC homeostasis, including increased expression of and responsiveness to the chemokine CCL20. Further, our data suggest the BRAFV600E-dependent production of the pleiotropic cytokine CCL7 is a potential driver of the inflammatory lesions in PLCH. Finally, we demonstrate that the BRAF mutation induces DC senescence accompanied by upregulation of non-classical MHC ligands that permit the DCs to evade immune-mediated clearance. Based on these novel preliminary data, we hypothesize that PLCH pathogenesis is initiated by a combination of BRAF mutations along with CS exposure to amplify CCL20 mediated histiocyte accumulation followed by the recruitment of inflammatory cells/nodule development via CCL7 production and the amplification of this process is preserved by BRAF-dependent expression of ligands for inhibitory receptors on cytotoxic lymphocytes. We will test this hypothesis with three inter-related, yet independent, Specific Aims. We expect the completion of the research will lead to new conceptual advances in PLCH. While PLCH is rare, we believe the preclinical model will lead to insights into the role of BRAFV600E cells in PLCH. This model provides a compelling platform for preclinical studies in the short term and evidence based clinical trials in the long term, and should enable the development of treatments of a life threatening pulmonary disease. This goal may be viewed as aggressive but the identification of an effective treatment for lymphanioleiomyomatosis by our group and promising clinical trials underway by our group as part of the Rare Lung Disease Consortium, are direct evidence that effective therapies can be found quickly when clues of nature are abundant, molecular targets are known, biological plausibility is high and patient communities are well organized.

项目摘要。肺朗格汉斯细胞组织细胞增生症（PLCH）是一种罕见的间质性肺病， 几乎只发生在吸烟者中， 12.5年PLCH的特征在于Langerin+树突状细胞（DC）积聚、炎性病变， 结节形成和囊性重塑。最近，获得性BRAF（ 骨髓/单核细胞谱系中RAS通路）突变与良性肿瘤的发生 已经报道，并且在肺损伤中发现了BRAF中常见的获得性突变（V600 E）， 超过一半的PLCH患者虽然这一因果联系是一个重要的突破， 突变型组织细胞控制PLCH发生和发展的机制尚不清楚。到 为了解决这一关键的知识缺口，我们开发了临床前模型， PLCH的特点我们发现，表达诱导型T细胞的小鼠暴露于香烟烟雾（CS）中， CD 11 c+细胞中的BRAFV 600 E突变表现出细支气管周围炎症、结节形成， 空域扩大伴随着囊肿样的形成。这些结构性变化伴随着 通过改变DC稳态，包括增加的表达和反应性， 趋化因子CCL 20。此外，我们的数据表明，BRAFV 600 E依赖性多效性的产生， 细胞因子CCL 7是PLCH中炎性损伤的潜在驱动因素。最后，我们证明， BRAF突变诱导DC衰老，伴随非经典MHC配体的上调， 允许DC逃避免疫介导的清除。根据这些新的初步数据，我们 假设PLCH发病机制是由BRAF突变沿着CS启动 暴露于扩增CCL 20介导的组织细胞积聚，随后募集炎性细胞， 细胞/结节的发展通过CCL 7的生产和扩增这一过程是保存 细胞毒性淋巴细胞上抑制性受体配体的BRAF依赖性表达。我们将测试这个 假设有三个相互关联，但独立的具体目标。我们预计该项目将完成 研究将导致PLCH的新概念进展。虽然PLCH是罕见的，我们认为临床前 该模型将有助于深入了解BRAFV 600 E细胞在PLCH中的作用。该模型提供了一个令人信服的 短期临床前研究平台和长期循证临床试验平台，以及 应该能够开发威胁生命的肺部疾病的治疗。这一目标可能是 被认为是侵略性的，但我们确定了一种有效的治疗淋巴管平滑肌瘤病， 作为罕见肺部疾病联盟的一部分，我们的小组正在进行的有希望的临床试验， 是直接的证据，证明当自然界的线索丰富时， 分子靶点是已知的，生物相容性高，患者群体组织良好。