Investigation of sex variation in PD-1/pSTAT3/IL-17A signaling in sarcoidosis pathogenesis

结节病发病机制中 PD-1/pSTAT3/IL-17A 信号传导的性别变异研究

• 批准号: 10266230
• 负责人: Wonder P. Drake
• 金额: $ 85.77万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-23 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10266230
• 关键词: 3-Dimensional; African American; Age; Antibodies; Asthma; Bleomycin; Bronchoalveolar Lavage; CD4 Positive T Lymphocytes; Cells; Chronic; Clinical; Clinical Trials; Coculture Techniques; Collagen; Development; Disease; Disease Progression; Estradiol; Estrogen Receptor alpha; Estrogens; Etiology; FDA approved; Female; Fibroblasts; Foundations; Genes; Genetic Transcription; Granulomatous; Hormonal; Human; Immune; Immunologics; Immunology; Inflammation; Interleukin-17; Interleukin-6; Investigation; Lung; Lung Inflammation; Mediating; Membrane; Microarray Analysis; Molecular Biology; Morbidity - disease rate; Mus; Outcome; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Prevalence; Production; Progesterone; Publications; Pulmonary Fibrosis; Pulmonary Sarcoidosis; Pulmonary Valve Insufficiency; Race; Receptor Signaling; Reporting; Research Personnel; Respiratory physiology; STAT3 gene; Sarcoidosis; Scleroderma; Signal Pathway; Signal Transduction; Susceptibility Gene; T-Cell Receptor; Therapeutic; Translational Research; Treatment Efficacy; Variant; Wild Type Mouse; Woman; adaptive immune response; anti-PD-L1; anti-PD-L1 therapy; cytokine; design; experience; genome wide association study; in vivo; indium-bleomycin; innovation; male; men; mortality; mouse model; programmed cell death ligand 1; programmed cell death protein 1; protein expression; receptor; sex; targeted treatment; transcriptome; transcriptomics; translational medicine

Project Summary Sarcoidosis is a granulomatous disease of unknown etiology with striking disparities in clinical outcome. Approximately 60% of sarcoidosis patients will spontaneously resolve their disease, while the remaining subjects experience a gradual loss of lung function, from with ~15- 20% ultimately die. We previously reported that the strength of the adaptive immune response is an important factor in sarcoidosis clinical outcome. Prior investigations demonstrate increased Programmed Death-1 (PD-1) expression on CD4+ T cells in sarcoidosis patients experiencing disease progression. Our recent publication in Science Translational Medicine demonstrates that PD-1+CD4+ T cells have augmented IL-6 expression that induces pSTAT3 transcription, leading to increased expression of the pathogenic cytokines, IL-17A and TGF-β1. These cells upon co-culture with human lung fibroblasts induce collagen-1 production. The percentage of PD-1+CD4+ T cells is significantly higher in female sarcoidosis subjects, compared to males. These observations support the hypothesis that estrogen-mediated alteration in PD-1 pathway/IL-6/pSTAT3 signaling drive the female predominance in sarcoidosis loss of lung function. This proposal will delineate if the effects of estrogen on Th17 cell development are directly or indirectly mediated through PD-1 pathway signaling. We will also conduct in vivo investigations of the efficacy of currently FDA-approved therapeutics against PD-L1, PD-1, IL-6, pSTAT3 and IL-17A on reduction of collagen production. These analyses will serve as proof-of-concept investigations, thus laying the foundation for design of innovative clinical trials of effective therapeutics against pulmonary sarcoidosis progression according to sex.

项目摘要 结节病是一种病因不明的肉芽肿性疾病， 临床结果。大约60%的结节病患者会自发地解决他们的 疾病，而其余受试者经历肺功能的逐渐丧失，从约15- 20%最终死亡。 我们以前报道过，适应性免疫反应的强度是一个重要的 结节病临床结局的影响因素。先前的调查显示， 结节病患者CD 4 + T细胞上死亡-1（PD-1）的表达 进展我们最近在《科学转化医学》上发表的文章表明， PD-1+ CD 4 + T细胞具有增强的诱导pSTAT 3转录的IL-6表达， 导致致病性细胞因子IL-17 A和TGF-β1的表达增加。这些细胞 在与人肺成纤维细胞共培养时诱导胶原-1产生。的百分比 PD-1+ CD 4 + T细胞在女性结节病受试者中显著高于男性。 这些观察结果支持了雌激素介导的 PD-1通路/IL-6/pSTAT 3信号传导驱动结节病损失中的女性优势 肺功能。本实验旨在阐明雌激素对Th 17细胞的影响， 在某些情况下，PD-1信号通路直接或间接介导了PD-1信号通路。我们还将 对目前FDA批准的治疗药物的疗效进行体内研究， PD-L1、PD-1、IL-6、pSTAT 3和IL-17 A对减少胶原蛋白产生的作用。这些分析 将作为概念验证调查，从而为创新的设计奠定基础。 有效治疗肺结节病进展的临床试验 性