Microbial induction of sarcoidosis CD4+ T cell dysfunction

微生物诱导结节病 CD4 T 细胞功能障碍

• 批准号: 9043520
• 负责人: Gordon R Bernard
• 金额: $ 2.2万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-16 至 2016-04-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9043520
• 关键词: Activities of Daily Living; Adverse event; Antimycobacterial Agents; Azithromycin; Biopsy; Blinded; Bronchoalveolar Lavage; CD4 Positive T Lymphocytes; Caliber; Cell physiology; Chest; Chronic; Clinic; Clinical; Complex; Cryptococcus; Cutaneous; Cutaneous Sarcoidosis; Data; Detection; Disease; Double-Blind Method; Dyspnea; Ethambutol; Etiology; Foundations; Functional disorder; Genetic Transcription; Genus Mycobacterium; Granulomatous; Health; High-Throughput Nucleotide Sequencing; Immunologics; Inflammation; Interferons; Interleukin-2; Investigation; Leprosy; Lesion; Levaquin; Lung; Lung diseases; Lymph; Lymphocyte Function; Lymphocyte-Specific p56LCK Tyrosine Protein Kinase; Mediator of activation protein; Molecular; Mycobacteriophages; Mycobacterium tuberculosis; Natural History; Nature; Pathogenesis; Pathway interactions; Patients; Perception; Peripheral Blood Mononuclear Cell; Phase; Physiological; Placebo Control; Placebos; Prevalence; Process; Production; Pulmonary Sarcoidosis; Quality-of-Life Assessment; Questionnaires; Randomized; Recovery; Regimen; Reporter; Resolution; Respiratory physiology; Rest; Ribosomal RNA; Rifampin; Safety; Saints; Sarcoidosis; Seminal; Severity of illness; Specimen; Steroid therapy; Steroids; T cell anergy; T-Lymphocyte; Testing; Therapeutic; Toxic effect; Translating; Tuberculosis; Universities; Virulence Factors; Vital capacity; Walking; Withdrawal; X-Ray Tomography; abstracting; adaptive immunity; base; cohort; cytokine; experience; immune function; improved; infliximab; meter; microbial; mortality; mycobacterial; novel; open label; pulmonary function; respiratory; response; restoration

DESCRIPTION (provided by applicant): This proposal rests upon the hypothesis that mycobacterial induction of CD4+ T cell energy leads to loss of sarcoidosis pulmonary function. Use of antimycobacterial therapy normalizes expression of key mediators of CD4+ T cell function, such as p56Lck, leading to increased IL-2 and IFN� production, and restoration of lung function. The transformative nature of this proposal is that it allows us to translate molecular mechanisms identified at the bench to immune function within the host, and ultimately to a clinical endpoint associated with sarcoidosis mortality, absolute FVC. Phase I analysis of the eight subjects completing the CLEAR regimen revealed an increase in the absolute FVC of 0.42 liters, reflecting a mean increase in absolute FVC of 16% from baseline. The observed pulmonary improvement was accompanied by an increase in functional capacity and perception of dyspnea that exceeds current sarcoidosis therapeutic options, such as steroids and infliximab. These encouraging efficacy data has led us propose a multicenter, randomized, double-blind, placebo-controlled Phase II investigation of the effects of CLEAR regimen on subjects with chronic, active pulmonary sarcoidosis. Subjects will be required to have systemic responses to ESAT-6 for study entry. The primary endpoint will be change in absolute FVC. Secondary endpoints will include investigation of steroid-sparing effects of CLEAR regimen, assessments of 6MWD, SGRQ, chest tomography (CT) radiographic changes and effects on T cell biologic function through the induction of IL-2 pathway in sarcoidosis BAL and PBMC. In addition, we will use reporter mycophages to characterize viable mycobacteria within sarcoidosis BAL. The safety profile will be assessed through detection of adverse events and abnormal lab values. The 1o and 2o endpoints will be obtained over a six month interval, laying the foundation for a definitive Phase 3 investigation.

描述（由申请人提供）： 该提议基于以下假设：分支杆菌诱导CD 4 + T细胞能量导致结节病肺功能丧失。使用抗分枝杆菌治疗使CD 4 + T细胞功能的关键介质（如p56 Lck）的表达正常化，导致IL-2和IFN γ产生增加，并恢复肺功能。这一提议的变革性质是，它使我们能够将实验室确定的分子机制转化为宿主体内的免疫功能，并最终转化为与结节病死亡率（绝对FVC）相关的临床终点。对完成CLEAR方案的8例受试者进行的I期分析显示，绝对FVC增加0.42 L，反映绝对FVC较基线平均增加16%。观察到的肺部改善伴随着功能能力的增加和呼吸困难的感觉，超过了目前的结节病治疗选择，如类固醇和英夫利西单抗。这些令人鼓舞的疗效数据使我们提出了一项多中心、随机、双盲、安慰剂对照的II期研究，以评估CLEAR方案对慢性活动性肺结节病受试者的影响。要求受试者对ESAT-6有全身反应才能入组研究。主要终点为绝对FVC的变化。次要终点将包括CLEAR方案的类固醇节省效应研究、6 MWD、SGRQ、胸部断层扫描（CT）影像学变化评估以及通过诱导结节病BAL和PBMC中的IL-2通路对T细胞生物学功能的影响。此外，我们将使用报告噬菌体来表征结节病BAL中的活分枝杆菌。将通过检测不良事件和异常实验室值评估安全性特征。将在6个月的时间间隔内获得1 o和2 o终点，为最终的III期研究奠定基础。