Microbial induction of sarcoidosis CD4+ T cell dysfunction

描述(由申请人提供)：这项建议建立在分枝杆菌诱导的CD4+T细胞无能导致结节病肺功能丧失的假设之上。使用抗分枝杆菌治疗使CD_4+T细胞功能的关键介质如p56Lck的表达正常化，导致IL-2和干扰素�的产生增加，并恢复肺功能。这一建议的变革性本质是，它允许我们将在实验台上发现的分子机制转化为宿主体内的免疫功能，并最终达到与结节病死亡率相关的临床终点，即绝对FVC。在意向治疗分析中，经过8周的治疗，15名受试者的FVC绝对值比基线的2.43FVC增加了0.24L，�为0.81(p=0.028，配对t检验)。完成CLEAR方案的8名受试者显示绝对用力肺活量增加了0.42升，反映出绝对用力肺活量比基线平均增加了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，超过了目前结节病的治疗选择，如类固醇和英夫利昔单抗。这些令人鼓舞的疗效数据使我们建议进行一项多中心、随机、双盲、安慰剂对照的第二阶段调查，研究CLEAR方案对慢性活动性肺结节病患者的影响。受试者将被要求对ESAT-6有系统的反应才能进入研究。主要终点将是绝对FVC的变化。次要终点将包括评估6MWD、SGRQ、胸部断层摄影(CT)的变化以及通过诱导结节病BAL和PBMC中的IL-2途径对T细胞生物功能的影响。此外，我们将使用报告菌噬菌体来鉴定结节病BAL中活的分枝杆菌。将通过检测不良事件和异常的实验室数值来评估安全概况。10个和20个端点将在6个月的时间间隔内获得，为最终的第三阶段调查奠定基础。

DESCRIPTION (provided by applicant): This proposal rests upon the hypothesis that mycobacterial induction of CD4+ T cell anergy 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. In the intention-to-treat analysis, following 8 weeks of therapy the 15 subjects revealed an increase of 0.24 liters from the baseline absolute FVC of 2.43�0.81 (p=0.028, paired t-test). 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 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.