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: 10698155
• 负责人: Corey S Cutler
• 金额: $ 258.31万
• 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/10698155
• 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; Epithelium; 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; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Modality; Modeling; Monitor; Morbidity - disease rate; Mus; Organ; Organoids; Oxidative Phosphorylation; Pathogenesis; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; 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 cell infiltration; T cell therapy; T-Lymphocyte; Testing; Therapeutic; Time; Tissue Banks; Tissues; Transplantation; Treatment Protocols; Writing; cell type; cellular targeting; chronic graft versus host disease; conditional knockout; data management; diagnostic signature; drug testing; effector T cell; experimental study; 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.

概括 慢性GVHD（CGVHD）是晚期发病率，死亡率和器官功能受损的主要原因 同种异体造血干细胞移植（HCT）之后。它可以影响所有器官和组织， 包括肺部，该疾病被称为细支气管炎闭塞综合征（BOS）。 BOS是一个 HCT之后发生的进行性，不可逆且通常是致命的肺部疾病。 BOS大约发生 5-10％的HCT幸存者被认为是CGVHD的肺表现。大约10-15％ CGVHD患者将发展为BOS，不到15％的BOS患者存活5年。主要地点 BOS的炎症是小气道，最终导致纤维化。 CGVHD因未能实现而导致 移植后的免疫耐受性。导致公差失败的机制很复杂 并涉及多种细胞类型，但T细胞是该过程的核心。静止的T细胞优先使用 线粒体氧化磷酸化作为基础能。在急性GVHD中，暴露于宿主的供体T细胞 在炎症环境中，同种剂迅速区分和增殖，并具有生物能和 生物合成需求通过重新编程代谢和使用多种能源来满足。在CGVHD中， 新陈代谢的需求不太了解，但是由于免疫细胞增殖的高能量需求 在CGVHD中，专门阻止关键代谢途径的策略可能被证明是一种新颖的治疗策略。 在此计划中，我们专注于困扰CGVHD领域的关键问题。我们解决了 我们对人CGVHD发病机理的理解以及优先考虑下一代的能力 通过定义表征发展CGVHD和 询问CGVHD治疗方案成功和失败的机制。我们探索独特的 CGVHD发病机理和肺损伤修复的代谢需求以及对最严重的重点治疗 CGVHD的表现，BOS。我们采用新型的器官培养物和免疫基因组学来查明细胞 和BOS的抗原靶标。我们组建了一个合作，多学科团队，独特地准备 对该领域产生重大影响。