Mechanisms and Therapy of Chronic Graft-vs.-Host Disease

慢性移植物抗宿主病的机制和治疗

• 批准号: 10493794
• 负责人: Corey S Cutler
• 金额: $ 266.51万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10493794
• 关键词: 3-Dimensional; Acute Graft Versus Host Disease; Address; Affect; Alloantigen; Allogenic; Alveolar; Antigens; B-Lymphocytes; Bioenergetics; Biological Assay; Biological Markers; Biometry; Blood; Bronchiolitis Obliterans; Cell Communication; Cells; Chronic; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Coculture Techniques; Complex; Coupled; Defect; Disease; Dose; Energy-Generating Resources; Engineering; Epithelial; Epitopes; Equilibrium; Evolution; Exposure to; Failure; Fibrosis; Gene Expression; Gene-Modified; Guide RNA; Helper-Inducer T-Lymphocyte; Hematopoietic Stem Cell Transplantation; Human; Image; Immune; Immune Targeting; Immune Tolerance; Immunogenetics; Immunogenomics; Immunologic Monitoring; Immunologics; Individual; Inflammation; Interleukin-2; Link; Lung; Lung diseases; Mediator of activation protein; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Modality; Modeling; Monitor; Morbidity - disease rate; Mus; Organ; Organoids; Oxidative Phosphorylation; Pathogenesis; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Plague; Population; Prediction of Response to Therapy; Principal Investigator; Process; Proliferating; RNA library; Regulatory T-Lymphocyte; Resistance; Resolution; Rest; Risk; Site; Specificity; Structure of germinal center of lymph node; Syndrome; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Transplantation; Treatment Protocols; Treg therapy; base; cell type; cellular targeting; chronic graft versus host disease; conditional knockout; data management; diagnostic signature; drug testing; effector T cell; experimental study; immune resistance; in vitro regeneration; in vivo evaluation; inflammatory milieu; inhibitor; injury and repair; lung injury; lung regeneration; mortality; mouse model; multidisciplinary; novel; novel therapeutics; phase II trial; profiles in patients; progenitor; programs; responders and non-responders; response; single cell analysis; single-cell RNA sequencing; success; transcriptome; transplant survivor; treatment strategy

Summary Chronic GVHD (cGVHD) is the major cause of late morbidity, mortality and compromised organ function after allogeneic hematopoietic stem cell transplant (HCT). It can affect essentially all organs and tissues, including the lungs, where the disease is termed Bronchiolitis Obliterans Syndrome (BOS). BOS is a progressive, irreversible, and often fatal lung disease that occurs following HCT. BOS occurs in approximately 5-10% of HCT survivors and is considered the pulmonary manifestation of cGVHD. Approximately 10-15% of cGVHD patients will develop BOS, and less than 15% of BOS patients survive 5 years. The primary site of inflammation in BOS is the small airway, eventually leading to fibrosis. cGVHD results from a failure to achieve immune tolerance after transplant. The mechanisms responsible for the failure of tolerance are complex and involve multiple cell types, but T cells are central to this process. Resting T cells preferentially use mitochondrial oxidative phosphorylation as basal energy. In acute GVHD, donor T cells exposed to host alloantigen in an inflammatory environment rapidly differentiate and proliferate, with bioenergetic and biosynthetic needs fulfilled by reprogramming metabolism and using multiple energy sources. In cGVHD, metabolism demands are less well understood, but with the high energy demands of proliferating immune cells in cGVHD, strategies to specifically block critical metabolic pathways may prove to be a novel treatment strategy. In this Program, we focus on the critical questions that plague the field of cGVHD. We address shortcomings in our understanding of the pathogenesis of human cGVHD and our ability to prioritize the next generation of therapeutic strategies by defining the immune networks that characterize patients who develop cGVHD and interrogate the mechanisms of both success and failure of cGVHD treatment regimens. We explore the unique metabolic demands in cGVHD pathogenesis and lung injury repair and focus therapeutics on the most severe manifestation of cGVHD, BOS. We employ novel organoid cultures and immunogenomics to pinpoint the cellular and antigenic targets of BOS. We have assembled a collaborative, multidisciplinary team, uniquely poised to make significant impact in the field.

总结 慢性移植物抗宿主病（cGVHD）是晚期发病、死亡和器官功能受损的主要原因 异基因造血干细胞移植（HCT）后。它基本上可以影响所有的器官和组织， 包括肺，其中该疾病被称为闭塞性细支气管炎综合征（BOS）。BOS是一个 HCT后发生的进行性、不可逆转且通常致命的肺部疾病。BOS发生在大约 5-10%的HCT存活者，被认为是cGVHD的肺部表现。约10-15% cGVHD患者将发展为BOS，并且少于15%的BOS患者存活5年。的原发部位 BOS中的炎症是小气道，最终导致纤维化。cGVHD是由于未能实现 移植后免疫耐受。导致耐受失败的机制是复杂的 涉及多种细胞类型，但T细胞是这个过程的核心。静息T细胞优先使用 线粒体氧化磷酸化作为基础能量。在急性GVHD中，暴露于宿主的供体T细胞 同种异体抗原在炎症环境中迅速分化和增殖，具有生物能量和 通过重新编程新陈代谢和使用多种能源来满足生物合成需求。在cGVHD中， 代谢需求不太清楚，但随着增殖免疫细胞的高能量需求， 在cGVHD中，特异性阻断关键代谢途径的策略可能被证明是一种新的治疗策略。 在这个项目中，我们专注于困扰cGVHD领域的关键问题。我们解决的缺点， 我们对人类cGVHD发病机制的理解和我们优先考虑下一代cGVHD的能力， 通过定义表征发展cGVHD的患者的免疫网络， 询问cGVHD治疗方案的成功和失败的机制。我们探索独特的 cGVHD发病机制和肺损伤修复中的代谢需求，并将治疗重点放在最严重的 表现为cGVHD、BOS。我们采用新的类器官培养和免疫基因组学来确定细胞 和BOS的抗原靶点。我们已经组建了一个协作的多学科团队， 在实地产生重大影响。