Impact of CCR5 inhibition on Sarcoid Immunophenotypes

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，其特征是形成非干酪性肉芽肿浸润物，最常见的是肺部。虽然结节病的具体原因尚不清楚，但这种疾病的肉芽肿形成和其他病理发现几乎肯定反映了遗传易感性个体对不明抗原的免疫反应失调。这一建议的主要假设是，对结节病患者的临床标本进行系统收集(特定目标1)和多学科研究(特定目标2)将导致对这种疾病的病因机制和预后生物标志物的识别的新见解。此外，我们还假设，在使用马拉韦罗的结节病患者中，CCRs的拮抗作用将安全地减少单核细胞和T细胞在肺内的迁移和隔离，减少这些细胞的激活和分化，并导致异常的、临床相关的炎症参数的可测量的改善(特定目标3)。这项建议的具体目的是1)收集结节病患者的残余淋巴结标本(纵隔镜和支气管镜引导下的细针活检[EBUS-FNA])、支气管肺泡灌洗液(BALF)、皮肤活检和外周血，以及详细的受试者临床数据(如人口统计学、疾病表型)，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对目标1收集的样本的部分/等位进行分析。这些研究将包括我们发现的与CD4T细胞激活和分化相关的蛋白质和基因表达(分别使用流式细胞术和RT-PCR)与其他慢性免疫性肺部疾病的预后高度相关；以及3)确定CCR5抑制对结节病患者CD4T细胞和单核/巨噬细胞的关键运输、激活和效应功能的影响。由此产生的数据将决定结节病患者要遵循的更明确的临床试验的设计，并将为CCR5抑制剂在结节病的潜在治疗用途提供洞察力。

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.