Understanding the role of Id2 in T cell differentiation and activation during GVHD

了解 Id2 在 GVHD 期间 T 细胞分化和激活中的作用

• 批准号: 10530575
• 负责人: Kayleigh Ingersoll
• 金额: $ 4.03万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10530575
• 关键词: Acute; Acute Graft Versus Host Disease; Address; Affect; Alloantigen; Antigens; Automobile Driving; Bone Marrow Transplantation; CRISPR/Cas technology; Cell Cycle Progression; Cell Transplantation; Cells; Cessation of life; Chromatin; Chronic; Clinic; Complication; Data; Data Set; Development; Diagnosis; Disease; Disease model; E protein; Epigenetic Process; FOXP3 gene; Functional disorder; Gene Expression; Genes; Goals; Hematologic Neoplasms; Hematological Disease; Hematopoietic Neoplasms; Homologous Transplantation; Human; ID2 gene; Immune response; Immunosuppressive Agents; In Vitro; Infection; Inflammation; Inflammatory Response; Lead; Literature; Malignant - descriptor; Malignant Neoplasms; Mediating; Modeling; Mus; Organ; Organ Transplantation; Pathogenesis; Pathogenicity; Pathology; Pathway Analysis; Pathway interactions; Patients; Play; Prevention; Process; Proliferating; Publishing; Regulation; Regulatory Pathway; Regulatory T-Lymphocyte; Relapse; Reporting; Risk; Role; T cell differentiation; T cell response; T-Lymphocyte; Testing; Time; Tissue Transplantation; Tissues; Transplant Recipients; Transplantation; chronic graft versus host disease; graft vs host disease; immune function; immune system function; immunoreaction; insight; interest; mortality; mortality risk; mouse model; nonhuman primate; novel; novel therapeutic intervention; pathogen; prevent; protective effect; targeted treatment; transcriptomics

Abstract Bone Marrow Transplantations (BMT) can be curative for a variety of hematologic malignancies but Graft Versus Host Disease (GVHD), an immune reaction of donor cells against the host, remains the deadliest risk of this therapy. T lymphocytes drive an inflammatory response in the host that can result in organ damage and destruction, and even death of the transplant recipient. While broad immunosuppressants are given to prevent and treat GVHD, it still results in the mortality of up to 50% after diagnosis. GVHD occurs in two forms, acute and chronic, that differ in their time to development as well as pathology. There is a need for more targeted therapies to prevent GVHD, while still maintaining the protective immune functions against pathogens and malignant relapse. We have used our highly translationally relevant non-human primate (NHP) model of GVHD to identify genes upregulated in T cells in target organs of GVHD. Through transcriptomic pathway analysis we have identified inhibitor of DNA-binding 2 (ID2) as a key upstream regulator of many genes activated in the destruction of target organs during GVHD. In the literature Id2 is involved in regulating T cell differentiation, but how this occurs and how it affects the functionality of T cells in the context of GVHD remains unknown. This project aims to understand how ID2 deletion in T cells affects their ability to differentiate into Type 1 and 17 (Th/c 1 and Th/c 17) T cells which drive GVHD and regulatory T cells (Treg) which prevent GVHD. We will use CRISPR/Cas9 to first delete ID2 in type 1 and 17 T cells and explore their functionality in vitro and in GVHD models. We will also assess how the regulatory landscape of ID2-edited T cells changes at baseline and in the context of GVHD through transcriptomic profiling. Second, we will delete ID2 from Treg cells to determine the effects of id2 in maintaining their suppressive activity. And we will evaluate the ability of ID2-delteted Treg cells to control GVHD, especially in cGVHD where Tregs play a vital role in suppressing conventional T cells in the long term. Targeting the pathogenicity of type 1 and 17 T cells while sparing the protective effects of T regulatory cells remains a challenge in the BMT field and the literature suggests that targeting ID2 may tip both towards tolerance. This project will be important in understanding better the role of ID2 in T cell differentiation and how targeting ID2 may represent a novel therapeutic strategy for controlling or treating GVHD.

抽象的 骨髓移植（BMT）可以治愈多种血液系统恶性肿瘤，但移植 宿主病（GVHD）是供体细胞对宿主的免疫反应，仍然是最致命的风险 治疗。 T淋巴细胞驱动宿主中的炎症反应，这可能导致器官损伤和 破坏，甚至是移植受者的死亡。虽然给予广泛的免疫抑制剂以防止 并治疗GVHD，诊断后仍会导致高达50％的死亡率。 GVHD以两种形式出现，急性 和慢性，这在发育时间和病理学的时间上有所不同。需要更多针对性的 预防GVHD的疗法，同时仍保持对病原体和病原体的保护性免疫功能 恶性复发。我们使用了GVHD的高度翻译相关的非人类灵长类动物（NHP）模型 确定GVHD目标器官中T细胞中上调的基因。通过转录途径分析我们 已经确定了DNA结合2（ID2）的抑制剂是激活了许多基因的关键上游调节剂 GVHD期间目标器官的破坏。在文献中，ID2参与调节T细胞分化，但 在GVHD背景下，这种情况的发生及其如何影响T细胞的功能仍然未知。这 项目旨在了解T细胞中的ID2删除如何影响其分化为1型和17的能力（TH/C 1和th/c 17）驱动GVHD和调节T细胞（TREG）的T细胞，可防止GVHD。我们将使用 CRISPR/CAS9首先删除1型和17个T细胞中的ID2，并在体外和GVHD中探索其功能 型号。我们还将评估ID2编辑的T细胞的调节景观如何在基线和在 通过转录组分析的GVHD上下文。其次，我们将从Treg单元中删除ID2来确定 ID2维持其抑制活性的影响。我们将评估ID2延伸的Treg细胞的能力 控制GVHD，尤其是在CGVHD中，Tregs在抑制常规T细胞中起着至关重要的作用 长期。靶向1型和17个T细胞的致病性，同时保留T调节的保护作用 细胞在BMT领域仍然是一个挑战，文献表明，靶向ID2可能两者都朝向 宽容。该项目对于更好地理解ID2在T细胞差异化以及如何方式方面将很重要 靶向ID2可能代表控制或治疗GVHD的新型治疗策略。