T resident memory cells in arthritis

关节炎中的 T 常驻记忆细胞

• 批准号: 10609770
• 负责人: Peter A Nigrovic
• 金额: $ 42.49万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10609770
• 关键词: 3-Dimensional; Adenoviruses; Adult; Affect; American; Animal Model; Antigens; Archives; Arthralgia; Arthritis; Award; Biology; CD8B1 gene; Cells; Cellular biology; Characteristics; Chemicals; Child; Chronic; Chronic Childhood Arthritis; Clinical; Coupled; Cytometry; Data; Development; Disease; Drug Eruptions; Flare; Flow Cytometry; Fluorescence; Foundations; Fresh Tissue; Functional disorder; Funding; Gold; Human; Image; Immune; Immunity; Immunofluorescence Immunologic; Individual; Inflammation; Inflammatory; Inflammatory Arthritis; Interruption; Intra-Articular Injections; Investigation; Joints; Lead; Life; Longterm Follow-up; LoxP-flanked allele; Mediating; Mediator of activation protein; Memory; Metabolism; Modification; Mus; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Patients; Pattern; Phenotype; Population; Positioning Attribute; Psoriasis; Recurrence; Reporter; Research; Resources; Rheumatoid Arthritis; Rheumatology; Role; SELL gene; Site; Skin; Stress; Surface; Synovial Membrane; System; T memory cell; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; anakinra; arthritis therapy; base; design; disability; disorder control; experimental study; in vivo; individual patient; inhibitor; irradiation; joint inflammation; joint injury; migration; mouse model; novel; novel strategies; ranpirnase; response; single-cell RNA sequencing; skin disorder; transcriptome

Project Summary Inflammatory arthritis in adults and children is often characterized by periods of quiescent activity followed by disease flares. In any individual patient, the same joints typically flare repeatedly, in a pattern that usually establishes itself early in disease and then persists for years or decades. The hypothesis of this proposal is that this “joint-specific memory” reflects the presence of T resident memory (TRM) cells, whose targeting represents a new approach to arthritis therapy. TRM are a recently-described subset of long-lived T cells, either CD8 and CD4, that develop in skin and other tissues as a response to tissue inflammation, persisting for years thereafter to provide long-lasting site-specific immunity. TRM have never been described in joints. We have now developed compelling evidence for the presence of these cells in human arthritic synovium using three orthogonal approaches: single-cell RNAseq, a novel 3-dimensional synovial culture system, coupled with cytometry by time of flight (CyTOF), and Mantra multidimensional immunofluorescence imaging. Further, we have developed or adapted three animal models to develop new murine systems optimized for the study of recurrent, joint-specific, T cell-dependent inflammatory arthritis. Building upon these preliminary data, we propose two specific aims. First, we will perform a comprehensive characterization of human synovial TRM with respect to surface phenotype, mediators, transcriptome, and metabolism to compare synovial TRM with synovial effector memory T cells and “gold standard” TRM from human skin. Second, we will use our animal models to characterize the development and persistence of TRM over time; to test the possibility that these cells can re-activate arthritis upon antigen-independent triggering as well as antigen exposure; and employ local depletion to test TRM targeting as a novel approach to durable joint-specific arthritis therapy.

项目概要 成人和儿童的炎症性关节炎通常以静止活动期为特征 随后是疾病爆发。在任何个体患者中，相同的关节通常会反复张开， 通常在疾病早期就形成这种模式，然后持续数年或数十年。这 该提案的假设是这种“关节特定记忆”反映了 T 的存在 常驻记忆（TRM）细胞，其靶向代表了关节炎治疗的新方法。 TRM 是最近描述的长寿 T 细胞的子集（CD8 和 CD4），在皮肤中发育 和其他组织作为对组织炎症的反应，此后持续数年以提供 持久的位点特异性免疫。 TRM 从未在关节中被描述过。我们现在有 使用以下方法开发了令人信服的证据来证明这些细胞在人类关节炎滑膜中的存在 三种正交方法：单细胞 RNAseq，一种新型的 3 维滑膜培养系统， 结合飞行时间细胞计数 (CyTOF) 和 Mantra 多维 免疫荧光成像。此外，我们开发或调整了三种动物模型 开发新的小鼠系统，优化用于研究复发性、关节特异性、T 细胞依赖性 炎症性关节炎。 根据这些初步数据，我们提出了两个具体目标。首先，我们将执行一个 人类滑膜 TRM 在表面表型方面的综合表征， 介质、转录组和代谢来比较滑膜 TRM 与滑膜效应记忆 T 细胞和来自人体皮肤的“黄金标准”TRM。其次，我们将使用我们的动物模型 描述 TRM 随着时间的推移的发展和持续性；来测试这些的可能性 细胞可以在不依赖于抗原的触发以及抗原暴露下重新激活关节炎；和 采用局部耗竭来测试 TRM 靶向作为治疗持久性关节特异性关节炎的新方法 治疗。