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.

项目摘要 成人和儿童的炎性关节炎通常以静止活动期为特征 然后是疾病爆发在任何个体患者中，相同的关节通常反复地张开， 这种模式通常在疾病早期建立，然后持续数年或数十年。的 这个提议的假设是，这种“关节特异性记忆”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是最近描述的长寿命T细胞的子集，CD 8和CD 4，在皮肤中发育 和其他组织作为对组织炎症的反应，持续多年， 持久的位点特异性免疫。TRM从未在关节中描述过。我们现在已经 开发了令人信服的证据，这些细胞存在于人类关节炎滑膜使用 三种正交方法：单细胞RNAseq，一种新的三维滑膜培养系统， 结合飞行时间流式细胞术（CyTOF）和Mantra多维 免疫荧光成像此外，我们已经开发或改造了三种动物模型， 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 炎性关节炎 在这些初步数据的基础上，我们提出了两个具体目标。首先，我们将执行一个 人滑膜TRM关于表面表型的综合表征， 介质、转录组和代谢，以比较滑膜TRM与滑膜效应记忆 T细胞和来自人类皮肤的“金标准”TRM。其次，我们将使用我们的动物模型， 描述TRM随时间的发展和持续性;测试这些 细胞可以在抗原非依赖性触发以及抗原暴露后重新激活关节炎;以及 采用局部耗竭测试TRM靶向作为持久性关节特异性关节炎的新方法 疗法