Chronic Granulomatous Disease: Determinants of Auto-Inflammation and Complications Following Hematopoietic Cell Transplantation

慢性肉芽肿病：造血细胞移植后自身炎症和并发症的决定因素

• 批准号: 10250418
• 负责人: Harry Malech
• 金额: $ 2.3万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-12 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10250418
• 关键词: Adhesions; Affect; Allogenic; Amines; Anaerobic Bacteria; Anti-Inflammatory Agents; Bacteremia; Biological Markers; Blood specimen; Butyrates; Chimerism; Chronic Granulomatous Disease; Clinical Trials; Colitis; Data; Data Set; Defect; Development; Diagnosis; Disease; Disease-Free Survival; Endothelium; Enrollment; Epithelial; Grant; Immune; In Vitro; Incidence; Individual; Infection; Inflammation; Inflammatory; Intestines; Lead; Liver; Lung; Metagenomics; Monitor; Mutation; NADPH Oxidase; Organ; Organism; Outcome; Oxides; Patient Outcomes Assessments; Patients; Pattern; Phagocytes; Plasma; Predisposition; Preparation; Production; Protocols documentation; Quality of life; Recording of previous events; Recurrence; Regimen; Research; Residual state; Resistance; Resolution; Retrospective Studies; Risk; Severities; Severity of illness; Sterility; Superoxides; Symptoms; Testing; Time; Transplantation; autoinflammation; autoinflammatory; biomarker signature; body system; clinical development; cohort; conditioning; congenital immunodeficiency; cytokine; fecal microbiome; gene therapy; graft vs host disease; gut microbiome; health related quality of life; hematopoietic cell transplantation; inflammatory disease of the intestine; metabolome; metabolomics; microbiome; microbiome signature; mortality; predictive marker; prospective; response; stool sample; therapy outcome; transplantation therapy

PIDTC Project 6908 CGD – Abstract Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by mutations in any of 5 subunits of the phagocyte NADPH oxidase. Patients are equally affected by infection susceptibility and immune dysregulation both in response to infection and presumed sterile inflammation. This auto-inflammation affects a variety of organ systems, particularly the bowel, lungs and liver. Uncontrolled auto-inflammation can be an indication for hematopoietic cell transplant (HCT) in CGD but retrospective studies suggest that patients with CGD undergoing HCT have a higher incidence of graft versus host disease (GVHD) and mortality if there is active infection or uncontrolled inflammation at the time of transplantation. The exact mechanism of auto- inflammation in CGD is unknown but several in vitro defects have been described. Lastly, studies of HCT indicate associations between GVHD and altered intestinal microbiome alpha diversity. Our prior studies show that 1) HCT can resolve CGD-associated colitis but history of colitis increases risk of GVHD; 2) the intestinal microbiome in CGD patients is altered at baseline with decreased alpha diversity, reduced colonization with anaerobic taxa associated with butyrate production and epithelial barrier protection, and 3) HCT significantly alters the CGD intestinal microbiome signature. We propose to prospectively enroll CGD patients who are planned to undergo HCT or gene therapy. We will longitudinally assess auto-inflammatory symptoms developing an auto-inflammatory disease score. In parallel, blood and stool samples will be assessed for cytokine alterations, metabolomics signatures, and the microbiome. Further, the 6908 protocol will provide opportunity to develop biomarkers of CGD-associated auto-inflammation. The objectives of this proposal are to advance the understanding of diagnosis and management of inflammatory symptoms in CGD in order to define how best to optimize HCT strategy to cure CGD and resolve auto-inflammatory symptoms post allogeneic HCT or gene therapy. With this cohort, we will 1) characterize and quantify auto-inflammatory symptoms that will determine an overall symptom score; 2) assess patient reported outcomes to understand how presence and resolution of auto-inflammation changes quality of life; 3) determine if HCT provides short and/or long term resolution of auto-inflammatory symptoms; 4) determine the optimal HCT strategy and what degree of donor chimerism is necessary to achieve and sustain resolution of auto-inflammatory symptoms; 5) determine biomarkers of CGD-associated auto-inflammation that can be predictive of symptom severity and control, and 6) determine metabolomics and metagenomics data of the stool microbiome in CGD patients and correlate how the biome influences post-HCT outcomes. The impact of the proposed research is that the longitudinal assessment and mechanistic studies we perform will optimize clinician practices and lead to development of clinical trials for CGD patients.

PIDTC项目6908 CGD -摘要 慢性肉芽肿病（CGD）是一种原发性免疫缺陷病，由5个 吞噬细胞NADPH氧化酶的亚基。患者同样受到感染易感性的影响， 对感染和假定的无菌炎症的免疫失调。这种自体炎症 影响多种器官系统，特别是肠、肺和肝。不受控制的自身炎症可以 是CGD中造血细胞移植（HCT）的适应症，但回顾性研究表明， 接受HCT的CGD患者的移植物抗宿主病（GVHD）发生率和死亡率较高， 是移植时的活动性感染或不受控制的炎症。自动化的确切机制 CGD中的炎症是未知的，但已经描述了几种体外缺陷。最后，HCT的研究 表明GVHD和改变的肠道微生物组α多样性之间的关联。我们之前的研究显示 1）HCT可以解决CGD相关的结肠炎，但结肠炎病史会增加GVHD的风险; 2）肠道 CGD患者的微生物组在基线时改变，α多样性降低， 厌氧类群与丁酸盐的产生和上皮屏障保护有关，3）HCT显著 改变CGD肠道微生物组特征。我们建议前瞻性招募符合以下条件的CGD患者： 计划进行HCT或基因治疗。我们将纵向评估自身炎症症状 发展出一个自身炎症性疾病评分。同时，将评估血液和粪便样本的 细胞因子改变、代谢组学特征和微生物组。第6908章还将继续 有机会开发CGD相关自身炎症的生物标志物。本提案的目标是 提高对CGD中炎症症状的诊断和管理的理解， 如何最好地优化HCT策略以治愈CGD并解决同种异体HCT后的自身炎症症状 或基因治疗。在这个队列中，我们将1）表征和量化自身炎症症状， 确定总体症状评分; 2）评估患者报告的结果，以了解患者的存在和 自身炎症的消退改变了生活质量; 3）确定HCT是否提供短期和/或长期的治疗; 自身炎症症状的解决; 4）确定最佳HCT策略和供体的 嵌合体是实现和维持自身炎症症状消退所必需的; 5）确定 可以预测症状严重程度和控制的CGD相关自身炎症的生物标志物，以及 6)确定CGD患者粪便微生物组的代谢组学和宏基因组学数据， 生物群系如何影响HCT后的结果。拟议研究的影响是， 我们进行的评估和机制研究将优化临床实践， CGD患者的临床试验。