Mechanisms, Prevention and Treatment of Chronic Graft-vs.-Host Disease

描述(由申请人提供)：慢性移植物抗宿主病(CGVHD)是异基因造血细胞移植(HCT)最重要的长期不良后果，也是最常见的死亡原因，发生在HCT后1-2年。在本项目支持的先前研究中，我们发现供者B细胞在cGVHD的病理生理学中起着关键作用。这在cGVHD患者和小鼠模型中都得到了证实，这导致我们进行了一系列临床试验，证明了B细胞导向疗法在治疗和预防cGVHD方面的临床疗效。本次更新的计划项目的首要目标是确定应用B细胞导向疗法治疗和预防慢性移植物抗宿主病的最佳策略。在这一合作努力中，我们纳入了新的关键多中心临床试验，cGVHD的临床前模型，以确定更有效的B细胞靶向策略，用于未来的临床研究和接受新疗法的患者的详细分析。这是一个高度整合的项目，项目1中的新临床试验是由项目2中先前的临床前小鼠研究和项目3中证明B细胞在cGVHD患者中的作用的实验室研究提供信息的。项目1以慢性移植物抗宿主疾病预防和治疗中的B细胞为目标，致力于抗B细胞疗法的临床试验，以解决cGVHD三个阶段中未得到满足的需求：临床前表现、初步治疗和晚期疾病。这些试验是我们先前工作的下一阶段研究，并由项目2的临床前研究提供信息。项目2，慢性GVHD预防和治疗的临床前药物方法致力于在cGVHD与纤维化相关的健壮小鼠模型中识别和测试cGVHD的新药和多肽疗法。项目3，慢性移植物抗宿主病的体液靶点和B细胞生物学致力于了解在项目1的临床试验中接受治疗的患者中B细胞定向治疗的免疫效果，以及这些新治疗方法改变体内B细胞功能的潜在机制。项目3中的新发现可能会导致cGVHD的新的生物标志物。在独特和高度集成的核心的支持下，我们有机会在以前发现的基础上再接再厉，改善cGVHD患者的预后。

DESCRIPTION (provided by applicant): Chronic GVHD (cGVHD) is the most important adverse long-term consequence of allogeneic hematopoietic cell transplantation (HCT) and represents the most frequent cause of mortality occurring after 1-2 years from HCT. In previous studies supported by this Program Project, we made the novel observation that donor B cells played a critical role in the pathophysiology of cGVHD. This was demonstrated in patients with cGVHD as well as in murine models and this led us to undertake a series of clinical trials that demonstrated the clinical efficacy of B cell-directed therapy in the treatment and prevention of cGVHD. The overarching goal of this Program Project in this renewal is to identify optimal strategies for the application of B cell-directed therapies for the treatment and prevention of cGVHD. In this collaborative effort, we incorporate novel pivotal multi-center clinical trials, preclinical models of cGVHD to identify more effective B cell targeting strategies for future clinical studies and detailed analysis of patients receiving novel therapies. This is a highly integrated Program Project where the new clinical trials in Project 1 have been informed by previous pre-clinical murine studies in Project 2 and laboratory studies demonstrating the role of B cells in patients with cGVHD in Project 3. Project 1, Targeting B Cells in Chronic Graft-versus-Host Disease Prevention and Treatment, is dedicated to clinical trials of anti-B cell therapy that address the unmet need during three phases of cGVHD: pre-clinical presentation, initial therapy and late stage disease. These trials are the next phase of studies leading from our prior work, and are informed by the preclinical studies of Project 2. Project 2, Preclinical Drug Approaches to Chronic GVHD Prevention and Treatment is dedicated to the identification and testing of new drug and peptide therapies of cGVHD in a robust mouse model of cGVHD associated with fibrosis. Project 3, Humoral Targets and B Cell Biology in Chronic Graft-vs.-Host Disease is dedicated to understanding the immunologic effects of B cell-directed therapies in patients treated on clinical trials in Project 1, and potential mechanisms by which these new treatments alter B cell function in vivo. Novel discovery in Project 3 may lead to new biomarkers of cGVHD. Supported by unique and highly integrated cores, we have the opportunity to build on our previous discoveries and improve outcomes for patients with cGVHD.