Biologic correlatives of chronic GVHD onset

项目摘要 异基因造血细胞移植（HCT）可以治愈许多血液系统癌症和其他生命周期疾病。 威胁血液系统疾病，但20-50%的幸存者发展为慢性移植物抗宿主病 移植物抗宿主病（cGVHD）是移植存活者发病和死亡的主要原因。在cGVHD中，供体的免疫力 细胞攻击患者，引起一系列事件，导致多形性多器官综合征 使人联想到自身免疫性疾病，如系统性硬化症、系统性红斑狼疮、干燥综合征， 综合征和扁平苔藓。慢性GVHD与生活质量差，功能状态受损， 并且需要用有效的免疫抑制剂进行长期治疗。有很多竞争对手 关于人类cGVHD病因学的假设，数据支持T和B细胞的参与， 巨噬细胞、树突细胞、成纤维细胞和内皮细胞。细胞因子、趋化因子和其他蛋白质 被牵连。据我们所知，尚未在cGVHD患者中研究微生物组。这个项目 将解决我们对人类cGVHD发展的理解中的关键差距： 在cGVHD临床发作前，皮肤、眼睛、口腔和血液中是否发生cGVHD？局部组织的早期变化 反映身体其他部位的变化，它们是否反映了cGVHD的病理生理学？我们能检测到 亚临床cGVHD使用新的测试策略，可能允许有针对性的先发制人的机会， 治疗？为了解决这些问题，我们将招募100名可评估的患者（80名来自Fred哈钦森，20名来自 美国国家癌症研究所）进行的一项前瞻性纵向研究，包括密集的双月评估。 通过“CATCH”研究（慢性GVHD的密切评估和测试），这个独特的队列将允许 让我们“观察”cGVHD在人类中的发展。除实体器官外，医学上无其他情况 移植为同种免疫反应的演变提供了一个类似的窗口， 与许多其他自身和同种免疫现象相关。参与者将在移植前接受研究，然后 从第3个月开始，每两个月一次，直至移植后第一年。评估包括物理 检查、症状测量和血液、结膜冲洗液、唾液和粪便取样。参与者 将在2-3个时间点接受皮肤和口腔活检，并进行光学相干断层扫描和其他检查。 每隔一个月对皮肤、眼睛和口腔进行一次专门的成像。细胞因子的生物学分析， 趋化因子、微生物组和细胞亚群将对信息样本进行检测， 在小鼠和人类系统中的观察，并产生新的假设。完成本项目 将促进我们对人类cGVHD生物学基础的理解，并指导治疗 基于对系统和组织特异性病理生理学的全面理解的方法， 以降低这种常见移植并发症的发病率和死亡率。

PROJECT SUMMARY Allogeneic hematopoietic cell transplantation (HCT) can cure many hematologic cancers and other life- threatening hematologic diseases, but 20-50% of survivors develop chronic graft-versus-host disease (cGVHD), the leading cause of morbidity and mortality in transplant survivors. In cGVHD, the donor's immune cells attack the patient setting up a cascade of events resulting in a pleomorphic multi-organ syndrome reminiscent of autoimmune diseases such as systemic sclerosis, systemic lupus erythematosus, Sjogren's syndrome, and lichen planus. Chronic GVHD is associated with poor quality of life, impaired functional status, and need for prolonged treatment with potent immunosuppressive agents. There are many competing hypotheses about the etiology of human cGVHD with data supporting involvement of T and B cells, macrophages, dendritic cells, fibroblasts and endothelial cells. Cytokines, chemokines and other proteins have been implicated. To our knowledge, the microbiome has not been investigated in cGVHD patients. This project will address key gaps in our understanding of human cGVHD development: what are the early events that occur in the skin, eyes, mouth, and blood before cGVHD clinical onset? Do early changes in local tissues mirror changes in the rest of the body, and do they reflect the pathophysiology of cGVHD? Can we detect subclinical cGVHD using new testing strategies, potentially allowing the opportunity for targeted pre-emptive treatment? To address these questions, we will enroll 100 evaluable patients (80 at Fred Hutchinson, 20 at the National Cancer Institute) in a prospective, longitudinal study involving intensive bimonthly assessments. Entitled the “CATCH” study (Close Assessment and Testing for Chronic GVHD), this unique cohort will allow us to “watch” cGVHD as it develops in humans. No other situation in medicine except solid organ transplantation provides a similar window into the evolution of an alloimmune response, and findings could be relevant to many other auto- and alloimmune phenomenon. Participants will be studied before transplant, then at bimonthly intervals through the first post-transplant year starting at month 3. Assessments include physical exams, symptom measurement, and sampling of blood, conjunctival washings, saliva, and feces. Participants will undergo skin and oral biopsies at 2-3 timepoints and also have optical coherence tomography and other specialized imaging of the skin, eyes, and mouth every other month. Biologic analyses of cytokines, chemokines, microbiome and cellular subsets will be performed on informative samples to test prior observations in the murine and human systems and to generate new hypotheses. Completion of this project will advance our understanding of the biologic underpinnings of human cGVHD and guide therapeutic approaches based on a comprehensive understanding of systemic and tissue-specific pathophysiology, in order to decrease the morbidity and mortality of this common transplant complication.