Impact of CCR5 inhibition on Sarcoid Immunophenotypes

CCR5 抑制对结节病免疫表型的影响

• 批准号: 8265084
• 负责人: STEVEN R DUNCAN
• 金额: $ 15.14万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8265084
• 关键词: Adverse effects; Affect; Aliquot; Antigens; Biological Assay; Biological Markers; Biopsy; Bronchoalveolar Lavage Fluid; CCR5 gene; CD4 Positive T Lymphocytes; Cell Differentiation process; Chronic; Chronic lung disease; Clinical; Clinical Data; Clinical Trials; Collection; Core Facility; Data; Disease; Etiology; Fine needle aspiration biopsy; Flow Cytometry; Gene Expression; Genomics; Granuloma; Granulomatous; Human; Immigration; Immune response; Immunologics; Immunophenotyping; Individual; Inflammatory; Informatics; Institution; Lung; Lung diseases; Measurable; Measures; Mediastinoscopy; Modification; Molecular Biology; Mononuclear Leukocytes; Organ; Pathologic; Patients; Phenotype; Pilot Projects; Population; Proteins; Research; Research Infrastructure; Research Personnel; Residual state; Reverse Transcriptase Polymerase Chain Reaction; Safety; Sampling; Sarcoidosis; Shapes; Skin; Specimen; Staging; Steroids; Structure of parenchyma of lung; System; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic Uses; Ultrasonography; clinically relevant; cohort; demographics; design; experience; in vivo; inhibitor/antagonist; insight; lymph nodes; macrophage; monocyte; multidisciplinary; novel; outcome forecast; patient population; peripheral blood; prognostic; protein expression; research study; sample collection; success; trafficking

DESCRIPTION (provided by applicant): Sarcoidosis is a chronic multi-system disease of unknown etiology characterized by formation of noncaseating granulomatous infiltrates, most often within the lungs. While the specific causality of sarcoidosis is enigmatic, the granuloma formation and other pathologic findings of this disorder almost certainly reflect a dysregulated immune response to an unidentified antigen among genetically predisposed individuals. The primary hypothesis of this proposal is that systematic collection (Specific Aim 1) and multidisciplinary study of clinical specimens from sarcoidosis patients (Specific Aim 2) will result in new insights into the etiopathogenesis of this disease and identification of prognostic biomarkers. In addition, we also hypothesize that CCRS antagonism in sarcoidosis patients with maraviroc will safely diminish the intrapulmonary immigration and sequestration of monocytes and T-cells, decrease activation and differentiation of these cells, and result in measurable Improvements of abnormal, clinically-relevant inflammatory parameters (Specific Aim 3). The specific aims of this proposal are 1) To collect residual lymph node specimens (mediastinoscopy and endobronchial ultrasound guided fine needle aspirations [EBUS-FNA]), bronchoalveolar lavage fluid (BALF), skin biopsies, and peripheral blood of sarcoidosis subjects, along with detailed subject clinical data (e.g., demographics, disease phenyotyping) for provision to the collaborative Genomic and Informatics Center (GIC); 2) To analyze portions/aliquots of the specimens collected in Aim 1 In immunobiological phenotyping assays. These studies will include measures of protein and.gene expressions related to CD4 T-cell activation and differentiation (using flow cytometry and RT-PCR, respectively) that we have discovered are highly associated with the prognosis of other chronic immunological lung diseases; and 3) To determine effects of CCR5 inhibition on key trafficking, activation, and effector functions of CD4 T-cells and monocytes/macrophages of sarcoidosis patients. The resultant data will shape the design of more definitive clinical trials i sarcoidosis patients to follow, and will provide insight on potential therapeutic uses of CCR5 inhibitors in sarcodosis.

描述（由申请人提供）： 结节病是一种病因不明的慢性多系统疾病，以非干酪化性肉芽肿性浸润形成为特征，最常见于肺内。虽然结节病的具体因果关系是谜，肉芽肿形成和其他病理结果，这种疾病几乎肯定反映了失调的免疫反应，一个不明抗原的遗传易感个体。该提案的主要假设是系统收集（具体目标1）和多学科研究结节病患者的临床标本（具体目标2）将导致对这种疾病的发病机制和预后生物标志物的鉴定的新见解。此外，我们还假设，在结节病患者中，马拉韦罗的CCRS拮抗作用将安全地减少单核细胞和T细胞的肺内迁移和隔离，减少这些细胞的活化和分化，并导致异常的临床相关炎症参数的可测量改善（具体目标3）。本提案的具体目的是1）收集结节病受试者的残留淋巴结标本（纵隔镜检查和支气管内超声引导细针抽吸[EBUS-FNA]）、支气管肺泡灌洗液（BALF）、皮肤活检和外周血，沿着详细的受试者临床数据（例如，人口统计学、疾病表型分型）以提供给协作基因组和信息学中心（GIC）; 2）在免疫生物学表型分析中分析目标1中收集的样本的部分/等分试样。这些研究将包括与CD 4 T细胞活化和分化相关的蛋白质和基因表达的测量（分别使用流式细胞术和RT-PCR），我们已经发现这些蛋白质和基因表达与其他慢性免疫性肺病的预后高度相关;以及3）确定CCR 5抑制对结节病患者的CD 4 T细胞和单核细胞/巨噬细胞的关键运输、活化和效应功能的影响。由此产生的数据将塑造更明确的结节病患者临床试验的设计，并将提供有关CCR 5抑制剂在结节病中的潜在治疗用途的见解。