T resident memory cells in arthritis

关节炎中的 T 常驻记忆细胞

基本信息

批准号：
10179324
负责人：
Peter A Nigrovic
金额：
$ 39.4万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10179324
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/antagonist irradiation joint inflammation joint injury migration mouse model novel novel strategies ranpirnase response single-cell RNA sequencing skin disorder transcriptome

项目摘要

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症性关节炎通常以静止活性为特征其次是疾病耀斑。在任何个人患者中，相同的关节通常会反复爆发通常在疾病早期建立自己的模式，然后持续数年或几十年。该提议的假设是，这种“特定于联合的记忆”反映了T的存在居民记忆（TRM）细胞，其靶向代表了一种新的关节炎治疗方法。 TRM是最近描述的长寿命T细胞的子集CD8和CD4，在皮肤中发展和其他时间安排作为对组织注射的反应，此后持续多年长期持久部位特异性免疫力。 TRM从未在关节中描述过。我们现在有开发了令人信服的证据，证明了这些细胞在人类关节节中的存在三种正交方法：单细胞RNASEQ，一种新型的三维滑膜培养系统，通过飞行时间（cytof）和咒语多维结合细胞仪免疫荧光成像。此外，我们已经开发或改编了三个动物模型开发针对复发，特异性，T细胞依赖性的研究优化的新鼠系统炎症性关节炎。在这些初步数据的基础上，我们提出了两个具体目标。首先，我们将执行人类滑膜TRM相对于表面表型的全面表征，介体，转录组和代谢，将滑膜TRM与滑膜效应器记忆进行比较 T细胞和人类皮肤的“金标准” TRM。其次，我们将使用我们的动物模型表征TRM随着时间的推移的发展和持久性；测试这些可能性细胞可以在抗原独立触发和抗原暴露时重新激活关节炎。和员工本地部署以测试TRM靶向作为一种耐用联合关节炎的新方法治疗。