Bronchiolitis Obliterans: Discovery and Therapy

项目摘要-项目3 闭塞性细支气管炎综合征(BOS)是一种进行性的、不可逆转的、通常是致命的肺部疾病 异基因造血细胞移植(HCT)后。BOS发生在大约5%-10%的Hct 是慢性移植物抗宿主病(CGVHD)的肺部表现。大约10%-15% 6%的cGVHD患者发生BOS，存活5年的BOS患者不足15%。初级免疫学 BOS的发病焦点是小气道，导致病理性纤维化。BOS没有治愈方法，治疗选择 是有限的。人们对BOS的病理生理学知之甚少。肺器官培养的创新和 免疫基因组学提供了一种精确定位BOS的细胞和抗原靶点的方法，我们的小鼠模型 事实证明，BOS在确定治疗这种疾病的有前景的疗法方面具有非常宝贵的价值。鉴于这些进步，在这方面 项目中，我们假设我们可以用一种有希望的药物来逆转BOS，这种药物可以 免疫功能失调，减少纤维化，同时从根本上提高我们对 利用体外模型确定免疫细胞和抗原靶点的BOS病理生理学研究 在BOS发动攻击。 我们将通过在患有BOS的受试者中进行新型药物KD025的临床试验来检验这些假说。 KD025是一种ROCK2抑制剂，其作用机制最初由本课题组破译和测试。这 该药物在cGVHD治疗和特发性肺纤维化治疗中显示出良好的活性。第二阶段试验将 通过NIH cGVHD反应标准确定BOS反应率，在一组新的 在KD025的24周疗程后，出现BOS和类固醇难治性BOS。在这次试验中，我们还将测试 基于CT扫描的参数反应图可作为BOS的影像生物标记物。 使用KD025试验中接受治疗的受试者的样本，我们将建立一个呼吸道有机物(AO)平台 探讨BOS的发病机制和治疗途径。利用AO，我们将研究细胞损伤和细胞-细胞 在BOS中的相互作用，我们将测试AO是否可以作为治疗反应的指标 毒品。肺浸润性CD4+T细胞在BOS病理生物学中的确切作用尚不清楚；使用切割法 边缘免疫基因组学，我们将确定BOS免疫攻击的抗原决定因素，并询问 用单细胞TCR测序和RNA-seq分析BOS中的转录程序。

Project Summary – Project 3 Bronchiolitis Obliterans Syndrome (BOS) is a progressive, irreversible, and often fatal lung disease that occurs following allogeneic hematopoietic cell transplantation (HCT). BOS occurs in approximately 5-10% of HCT survivors and is the pulmonary manifestation of chronic graft-vs.-host disease (cGVHD). Approximately 10-15% of cGVHD patients develop BOS, and less than 15% of BOS patients survive 5 years. The primary immunologic focus of attack in BOS is the small airway, leading to pathologic fibrosis. BOS has no cure, and treatment options are limited. Little is known about the pathophysiology of BOS. Innovations in lung organoid culture and immunogenomics offers a means to pinpoint the cellular and antigenic targets of BOS, and our murine model of BOS has proven invaluable in identifying promising therapeutics for this disease. Given these advances, in this Project, we hypothesize that we can reverse BOS with a promising pharmacologic agent that addresses dysregulated immunity and reduces fibrosis while fundamentally improving our understanding of the pathophysiology of BOS by using in vitro models to identify the cellular and antigenic targets of immunologic attack in BOS. We will test these hypotheses by performing a clinical trial of the novel agent, KD025, in subjects with BOS. KD025 is a ROCK2 inhibitor whose mechanism of action was initially deciphered and tested by our group. This agent has shown promising activity in cGVHD therapy and in idiopathic pulmonary fibrosis. A phase II trial will determine the BOS response rate, measured by NIH cGVHD Response Criteria, in a cohort of subjects with new onset and steroid-refractory BOS, following a 24-week course of KD025. In this trial we will also test whether CT-scan based parametric response mapping can act an imaging biomarker in BOS. Using samples from subjects being treated on the KD025 trial, we will establish an airway organoid (AO) platform to study mechanisms and therapeutic avenues for BOS. Using AO, we will study cellular injury and cell-cell interactions in BOS, and we will test whether AO can serve as treatment response indicators to therapeutic drugs. The precise role of lung-infiltrating CD4+ T cells in the pathobiology of BOS is unknown; using cutting edge immunogenomics, we will identify the antigenic determinants of immune attack in BOS and interrogate the transcriptional programs in BOS using single-cell TCR sequencing and RNA-seq analysis.