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) 可治愈多种血液系统恶性肿瘤，但移植与移植 宿主疾病（GVHD）是供体细胞针对宿主的免疫反应，仍然是这种疾病最致命的风险 治疗。 T 淋巴细胞在宿主体内驱动炎症反应，从而导致器官损伤和 破坏，甚至移植受者的死亡。虽然给予广泛的免疫抑制剂来预防 并治疗GVHD，诊断后仍导致高达50%的死亡率。 GVHD 有两种形式发生：急性 和慢性，其发育时间和病理学有所不同。需要更有针对性 预防 GVHD 的疗法，同时仍保持针对病原体的保护性免疫功能和 恶性复发。我们使用了高度翻译相关的非人灵长类动物 (NHP) GVHD 模型 鉴定 GVHD 靶器官中 T 细胞上调的基因。通过转录组通路分析我们 已确定 DNA 结合 2 (ID2) 抑制剂是许多基因激活的关键上游调节因子 GVHD 期间靶器官的破坏。文献中Id2参与调节T细胞分化，但是 这是如何发生的以及它如何影响 GVHD 背景下 T 细胞的功能仍然未知。这 该项目旨在了解 T 细胞中 ID2 缺失如何影响其分化为 1 型和 17 型（Th/c 1 和 Th/c 17) 驱动 GVHD 的 T 细胞和预防 GVHD 的调节性 T 细胞 (Treg)。我们将使用 CRISPR/Cas9 首先删除 1 型和 17 T 细胞中的 ID2，并探索它们在体外和 GVHD 中的功能 模型。我们还将评估 ID2 编辑的 T 细胞的监管环境在基线和治疗过程中如何变化。 通过转录组分析了解 GVHD 的背景。其次，我们将从Treg细胞中删除ID2以确定 id2 在维持其抑制活性方面的作用。我们将评估 ID2 缺失的 Treg 细胞的能力 控制 GVHD，特别是在 cGVHD 中，Treg 在抑制传统 T 细胞方面发挥着至关重要的作用 长期。针对 1 型和 17 型 T 细胞的致病性，同时保留 T 调节的保护作用 细胞仍然是 BMT 领域的一个挑战，文献表明靶向 ID2 可能会朝着两个方向发展： 宽容。该项目对于更好地理解 ID2 在 T 细胞分化中的作用以及如何发挥作用非常重要。 靶向ID2可能代表一种控制或治疗GVHD的新治疗策略。