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.

项目总结/摘要 结节病是一种病因不明的全身性肉芽肿性疾病，可累及多个器官，尤其是 肺它具有广泛的临床结局，包括进行性肺部疾病和多器官 参与。由于缺乏可靠或有效的标志物，结节病表现出许多 这是对临床医生的挑战，特别是考虑到用作治疗的免疫抑制疗法的毒性。 我的目标是这个K23奖是确定如何特定的免疫细胞和蛋白质与系统器官 结节病患者的负荷和肺功能。在实现这一目标的同时，我将追求一个严格的 职业发展计划，以扩大我在临床研究方法和T细胞生物学的技能。血液指标 我将研究与IFN-γ的生物学联系，IFN-γ是结节病炎症中的一种重要细胞因子。这些标记 包括：1）可产生大量IFN-γ的特定T辅助细胞亚群，和2） 由IFN-γ诱导的趋化因子，其将免疫细胞运送到发炎组织。我已经生成了初步数据 这些标志物使用了一个良好的表型纵向结节病队列，由我的主要导师， 劳拉·科思感兴趣的T细胞群通过转录因子T-bet的产生来定义， 调节IFN-γ的产生。使用多参数流式细胞术，我鉴定了一群T辅助细胞， 具有明显高水平的T-bet蛋白（T-betHi细胞）。这些T-betHi细胞几乎只存在于 受试者的肺功能测试（PFT）下降。这些细胞的初步体外试验表明，它们具有 产生IFN-γ的能力非常高。目的1将确定这些T-betHi细胞中IFN-γ的产生如何 与其潜在的致病性有关。第二组标记物包括三种IFN-γ诱导的趋化因子 （CXCL 9、CXCL 10和CXCL 11），这是我最近两篇出版物的主题。我展示了血清 这些趋化因子的水平与肺功能的纵向变化和器官损伤有明显的相关性。 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。因此，在目的2和3中，我将确定T-betHi细胞和这些趋化因子的关系 两个结节病队列的结果。我一直在帮助科思博士招募受试者进入这些队列， 研究访视，以收集我将在本提案中使用的临床数据。这些队列包括新患有 已确诊的疾病，并在长达两年的时间内重复随访。我会确定这些标记 与受累器官数量（目标2）和肺功能（目标3）纵向相关。除了提供 直接参与这些队列，Koth博士将分享她的实验室空间，并提供支持，以衡量这些 血液标记我也将受益于临床研究和生物统计学和我的共同导师的专业知识， Drs.伍德拉夫和艾伦。作为我培训计划的一部分，我将补充我在硕士期间获得的技能 在临床研究通过额外的流行病学和统计学课程。在这个奖项，我将产生 申请R 01资助，成为独立资助的临床和转化研究人员。

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