Using high T-bet-expressing cells and Serum Chemokines as Indicators of Disease Severity in Sarcoidosis

使用高 T-bet 表达细胞和血清趋化因子作为结节病疾病严重程度的指标

• 批准号: 10684920
• 负责人: Nicholas Kostandinos Arger
• 金额: $ 17.98万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10684920
• 关键词: Affect; Antigens; Award; Biologic Characteristic; Biological; Biological Markers; Biology; Biometry; Blood; Bronchoalveolar Lavage; CD4 Positive T Lymphocytes; CXCL10 gene; CXCL11 gene; CXCL9 gene; Cell Separation; Cells; Cellular Assay; Cellular biology; Chronic; Chronic Disease; Clinical; Clinical Data; Clinical Research; Data; Development Plans; Disease; Disease Marker; Disease Outcome; Enrollment; Epidemiology; Etiology; Eye; Flow Cytometry; Funding; Goals; Grant; Granuloma; Granulomatous; Granulomatous disease; Heart; Helper-Inducer T-Lymphocyte; Immune; Immunologics; Immunology; Incidence; Infiltration; Inflammation; Inflammatory; Interferon Type II; Interferons; Kidney; Life; Light; Link; Liver; Longitudinal cohort; Lung; Lung diseases; Measures; Memory; Mentored Patient-Oriented Research Career Development Award; Mentors; Modeling; Monitor; Morbidity - disease rate; Natural History; Nervous System; Newly Diagnosed; Newly Diagnosed Disease; Organ; Outcome; Pathogenicity; Patients; Pattern; Phenotype; Population; Production; Property; Proteins; Publications; Pulmonary function tests; Research; Research Methodology; Risk; Running; Sarcoidosis; Serum; Severities; Severity of illness; Signaling Protein; Site; Skin; Source; Spleen; Surface; T memory cell; T-Lymphocyte; T-bet protein; Testing; Therapeutic immunosuppression; Time; Tissues; Toxic effect; Training; Training Activity; Visit; biomarker validation; career development; cell motility; chemokine; cohort; cytokine; experience; follow-up; in vitro Assay; individual patient; interest; mortality; novel; pulmonary function; response; skills; statistics; time use; tool; translational scientist

PROJECT SUMMARY/ABSTRACT Sarcoidosis is a systemic granulomatous disease of unknown etiology that affects multiple organs, especially the lungs. It has a wide range of clinical outcomes, including progressive lung disease and multi-organ involvement. Due to the lack of reliable or validated markers for these outcomes, sarcoidosis presents many challenges to clinicians, especially in light of the toxicities from immunosuppressive therapies used as treatment. My goal for this K23 award is to determine how specific immune cells and proteins relate to systemic organ burden and pulmonary function in sarcoidosis patients. While accomplishing this goal, I will pursue a rigorous career development plan to expand my skills in clinical research methods and T cell biology. The blood markers I will study are biologically linked to IFN-γ, an essential cytokine in sarcoidosis inflammation. These markers include: 1) a specific subset of T helper cells that can produce high amounts of IFN-γ and 2) serum levels of chemokines induced by IFN-γ that traffic immune cells to inflamed tissues. I have generated preliminary data for these markers using a well-phenotyped longitudinal sarcoidosis cohort established by my primary mentor, Dr. Laura Koth. The T cell population of interest is defined by production of the transcription factor T-bet, which regulates IFN-γ production. Using multi-parameter flow cytometry, I identified a population of T helper cells that have distinctly high levels of T-bet protein (T-betHi cells). These T-betHi cells were present almost exclusively in subjects with pulmonary function test (PFT) declines. Initial in vitro assays of these cells suggest that they have exceptionally high capacity to produce IFN-γ. Aim 1 will determine how IFN-γ production in these T-betHi cells relates to their potential pathogenicity. The second group of markers includes three IFN-γ-induced chemokines (CXCL9, CXCL10, and CXCL11), which were the subject of two of my recent publications. I showed that serum levels of these chemokines had distinct associations with the longitudinal pulmonary function changes and organ involvement. These associations may be due to their underlying biology and therefore carry specific relevance in the disease. Thus, in Aims 2 and 3, I will determine the relationship of both T-betHi cells and these chemokines to outcomes in two sarcoidosis cohorts. I have been helping Dr. Koth enroll subjects into these cohorts and I run study visits to collect the clinical data I will use in this proposal. These cohorts include subjects with newly diagnosed disease who have repeated follow-up over up to two years. I will determine how these markers relate longitudinally to the number of organs affected (Aim 2) and pulmonary function (Aim 3). In addition to offering direct involvement with these cohorts, Dr. Koth, will share her lab space and provide support to measure these blood markers. I will also benefit from the clinical research and biostatistical and expertise of my co-mentors, Drs. Woodruff and Allen. As part of my training plan, I will supplement skills I have acquired during my Master's in Clinical Research through additional epidemiology and statistics coursework. During this award I will generate data to apply for R01 funding to become an independently funded clinical and translational researcher.

项目摘要/摘要 结节病是一种系统性病因的全身性肉芽肿，影响多个器官，尤其是 肺。它具有广泛的临床结果，包括进行性肺部疾病和多器官 参与。由于缺乏这些结果的可靠或验证标记，结节病呈现了许多 对临床医生的挑战，尤其是鉴于被用作治疗的免疫抑制疗法的毒性。 我获得K23奖的目标是确定特定的免疫细胞和蛋白质如何与全身器官相关 结节病患者的负担和肺功能。在完成这个目标时，我会严格 职业发展计划，以扩大我在临床研究方法和T细胞生物学方面的技能。血标记 我将研究在生物学上与IFN-γ相关，IFN-γ是结节病中必不可少的细胞因子。这些标记 包括：1）可以产生大量IFN-γ和2）血清水平的T辅助细胞的特定子集 IFN-γ诱导的趋化因子会导致交通免疫细胞发炎。我已经生成了初步数据 这些标记使用我的主要导师博士建立的精心型纵向结节病队列。 劳拉·科斯（Laura Koth）。感兴趣的T细胞种群由转录因子T-BET的产生定义 调节IFN-γ的产生。使用多参数流式细胞仪，我确定了T辅助细胞的群体 具有明显高水平的T-bet蛋白（T-bethi细胞）。这些T-bethi细胞几乎完全存在于 具有肺功能测试（PFT）的受试者下降。对这些细胞的初步体外评估表明它们具有 产生IFN-γ的能力异常高。 AIM 1将确定如何在这些T-bethi细胞中产生IFN-γ 与它们的潜在致病性有关。第二组标记包括三个IFN-γ诱导的趋化因子 （CXCL9，CXCL10和CXCL11），这是我最近的两个出版物的主题。我展示了连续的 这些趋化因子的水平与纵向肺功能变化和器官有不同的关联 参与。这些关联可能是由于其潜在的生物学，因此具有特定的相关性 在疾病中。在目标2和3中，我将确定T-Bethi细胞和这些趋化因子的关系 在两个结节病同伴中的结果。我一直在帮助Koth博士注册这些同伙，我跑步 研究访问以收集我将在此提案中使用的临床数据。这些队列包括新的主题 被诊断出的疾病，他们在长达两年的时间里重复进行了随访。我将确定这些标记如何相关 纵向到受影响的器官（AIM 2）和肺功能（AIM 3）。除了提供 Koth博士将直接参与这些队列，将分享她的实验室空间，并提供支持以衡量这些空间 血标记。我还将受益于我的临床研究，生物统计学和专业知识， 博士。伍德拉夫和艾伦。作为我的培训计划的一部分，我将补充我在主人期间获得的技能 通过其他流行病学和统计课程在临床研究中。在此奖励期间，我将产生 申请R01资金的数据成为独立资助的临床和翻译研究人员。

项目成果

Defining CD4 T helper and T regulatory cell endotypes of progressive and remitting pulmonary sarcoidosis (BRITE): protocol for a US-based, multicentre, longitudinal observational bronchoscopy study.

• DOI: 10.1136/bmjopen-2021-056841
• 发表时间: 2021-11-09
• 期刊: BMJ open
• 影响因子: 2.9
• 作者: Koth LL;Harmacek LD;White EK;Arger NK;Powers L;Werner BR;Magallon RE;Grewal P;Barkes BQ;Li L;Gillespie M;Collins SE;Cardenas J;Chen ES;Maier LA;Leach SM;O'Connor BP;Hamzeh NY
• 通讯作者: Hamzeh NY