GLILD in CVID

描述（由申请人提供）：常见变异性免疫缺陷（CVID）是临床上最重要的原发性免疫缺陷，因为其发病率高，并发症严重，治疗费用长。一种称为肉芽肿性/淋巴细胞性间质性肺病（GLILD）的间质性肺病（ILD）发生在10-15%的CVID患者中。根据我们的经验，GLILD可引起进行性限制性肺病，导致大量发病，是死亡的重要原因。GLILD的病因尚不清楚，没有长期的纵向研究确定GLILD的自然病程，也没有临床试验确定这种情况的最佳治疗方案。因此，GLILD的治疗尚无既定的护理标准。我们最近发现，利妥昔单抗（RTX），一种抗B细胞抗原CD 20的单克隆抗体，和一种抗-代谢物硫唑嘌呤（AZA）的免疫抑制治疗，改善了选定的GLILD患者队列的肺功能和胸部高分辨率CT（HRCT）扫描的放射学异常。鉴于这些令人鼓舞的结果，我们建议对GLILD患者进行一项多中心、安慰剂对照试验。研究患者将接受安慰剂或RTX和AZA治疗18个月。我们将测量治疗对肺功能和HRCT的影响。同时，我们将对GLILD患者或正常肺的开放肺活检进行RNA-seq，并确定GLILD患者的肺的转录组是否是不同的，并预测那些对RTX/AZA有反应或无反应的患者。我们将使用RNA-seq差异表达与称为PRICE（Paired-Read Iterative Contig Extension）的新型软件相结合，以筛选导致GLILD的潜在病原体的开放肺活检。最后，我们将确定外周血中DR+T细胞百分比的降低和TcB数量的增加是否是对RTX/AZA反应的预测因子。R34计划补助金的目标是：1）通过招募足够的研究者和研究中心，确保开展拟议试验的可行性; 2）制定开展试验的结构。这将包括但不限于领导结构的制定;临床和科学核心;法规文件;数据安全性监查委员会（DSMB）;程序手册（MOP）;以及用于收集数据的数据库，以确保科学和伦理的严格性; 3）就与拟定临床试验的三个目标相关的剩余临床和科学问题达成共识。

DESCRIPTION (provided by applicant): Common variable immunodeficiency (CVID) comprises the most clinically important primary immunodeficiency due to its prevalence, serious complications and long---term costs of therapy. A form of interstitial lung disease (ILD) known as granulomatous/lymphocytic interstitial lung disease (GLILD) occurs in 10---15% of patients with CVID. In our experience, GLILD causes progressive restrictive lung disease, leads to substantial morbidity, and is an important cause of death. The causes of GLILD are unknown, no long---term longitudinal study has defined the natural course of GLILD, and no clinical trials have been performed to define an optimal therapeutic regimen for this condition. Consequently, there is no established standard of care for the treatment of GLILD. We recently found that immunosuppressive therapy using rituximab (RTX), a monoclonal antibody against the B cell antigen CD20, and an anti---metabolite, azathioprine (AZA), improved the pulmonary function and radiographic abnormalities seen on high resolution CT (HRCT) scans of the chest in select cohort of patients with GLILD. Given these encouraging results, we propose a multicenter, placebo controlled trial for patients with GLILD. Study patients will receive either placebo, or RTX and AZA for 18 months. We will measure the effect of treatment on pulmonary function and HRCT. In parallel, we will perform RNA-seq on open lung biopsies of patients with GLILD or normal lung, and determine if the transcriptome of lungs of patients with GLILD are distinct and predictive of those patients that respond or don't respond to RTX/AZA. We will use RNA-seq differential expression in combination with novel software known as PRICE (Paired---Read Iterative Contig Extension) to screen open lung biopsies for potential pathogens that cause GLILD. Finally, we will determine if decreases in the percentage of DR+T cells, and increases in the number of Tregs in the peripheral blood, are predictors of response to RTX/AZA. The goals of the R34 planning grant are to: 1) Ensure feasibility of conducting the proposed trial by recruiting sufficient investigators and centers; 2) Develop the structure whereby the trial may be conducted. This will include, but not be limited to, development of a leadership structure; clinica and scientific cores; regulatory documents; Data safety monitoring board (DSMB); Manuals of Procedures (MOP); and databases for collection of data to ensure scientific and ethical rigor; 3) Establish a consensus on the remaining clinical and scientific issues as it relates to the three aims of the proposed clinical trial.