CD8 T Cells in Rheumatoid Arthritis

CD8 T 细胞在类风湿关节炎中的作用

• 批准号: 7186728
• 负责人: Cornelia M. Weyand
• 金额: $ 33.43万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7186728
• 关键词: Address; Adoptive Immunotherapy; Adoptive Transfer; Adverse effects; Affect; African American; Anti-Cytokine Therapy; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Antigens; Architecture; Biological Markers; CD4 Positive T Lymphocytes; CD8B1 gene; Candidate Disease Gene; Cell Therapy; Cell surface; Cells; Characteristics; Chimera organism; Complex; Condition; Confocal Microscopy; Data; Dendritic Cells; Disease; Disease Outcome; Disease-Modifying Second-Line Drugs; Doctor of Medicine; Enrollment; Evaluation; Event; Fibroblasts; Flow Cytometry; Frequencies; Funding; Future; Gene Expression; Genes; Goals; Hospitals; Human; Immune; Immune system; Immunosuppression; Immunosuppressive Agents; Immunotherapy; In Vitro; Individual; Inflammation; Joints; Kinetics; Lesion; Lymphocyte Function; Lymphoid; Mediating; Modeling; Molecular; Molecular Profiling; Monitor; Mus; NCAM1 gene; Outcome; Pathway interactions; Patients; Physiological; Play; Polymerase Chain Reaction; Pre-Clinical Model; Process; Production; Reagent; Receptor Signaling; Refractory; Registries; Research Personnel; Rheumatoid Arthritis; Risk; Role; Signal Transduction; Signaling Molecule; Signaling Protein; Societies; Suppressor-Effector T-Lymphocytes; Synovial Membrane; Synovitis; System; T-Lymphocyte; TNFRSF5 gene; Testing; Therapeutic immunosuppression; Time; Tissues; Universities; Western Blotting; angiogenesis; chemokine; cohort; design; follow-up; immunological synapse; in vivo; novel; novel therapeutics; prevent; prognostic; programs; prospective; release of sequestered calcium ion into cytoplasm; selective expression

DESCRIPTION (provided by applicant): Despite progress in anti-cytokine therapy the management of rheumatoid arthritis (RA) still requires continuous and aggressive immunosuppression, with a risk for severe side effects. This proposal is designed to explore the mechanisms through which CD8+CD28-CD56+ T suppressor cells inhibit rheumatoid synovitis and how they can be developed into a novel adoptive immunotherapy for this crippling disease Exploiting the preclinical model of human synovium-NOD-SCID chimeras we have identified the adoptive transfer of CD8+CD28-CD56+ T cell clones as a potent means of suppressing synovitis. In vivo and in vitro such CD8+CD28-CD56+ Ts cells downregulate the expression of the costimulatory molecule CD86 on synovial fibroblasts and other synovial APC. Here we hypothesize that CD8+CD28-CD56+ T cells induce unresponsiveness of CD4 T cells by tolerizinq APC in the synovial lesions of RA. leading to long-term inhibition of the disease. Specific Aim 1 is designed to identify the molecular mechanisms through which CD8+CD28-CD56+ Ts cells condition APCs to induce CD4 T cell unresponsiveness. Specific Aim 2 will examine how conditioned APC interact with CD4 T cells, whether a mature immunological synapse is induced and how transmembrane signaling events in CD4 T cells are different from normal activation. In particular, we will examine whether such CD4 T cells have the signature of anergic T cells with enhanced proteolytic degradation of specific signaling proteins In Specific Aim 3 we propose to seek for the critical molecules and pathways that convey immunosuppressive capability onto CD8+CD28-CD56+ T cells, including studies on the role of the CD56 molecule itself. In Specific Aim 4 we will explore whether these specialized CDS T cells have value as biomarkers in predicting disease course and outcome in prospectively followed patients with early RA. Relevance: Rheumatoid arthritis is a crippling disease that is mediated by the immune system. It can be treated but not cured and is costly for the affected individual and society. The immune system possesses cells that naturally inhibit immune-mediated inflammation. The goal of this proposal is to understand how such anti-inflammatory lymphocytes function and how they can be harnessed as novel therapeutic reagents in RA.

描述（由申请人提供）：尽管在抗周期疗法方面进展，类风湿关节炎（RA）的管理仍然需要连续且具有侵略性的免疫抑制，并有严重副作用的风险。该建议旨在探索CD8+ CD28-CD56+ T抑制细胞抑制类风湿滑膜炎以及如何将它们发展成一种新型的接收性免疫疗法，以利用这种残酷的疾病，利用人类Synovium-Nod-scid Chimeras的临床前模型，我们已经确定了cd8+ cd8+ cd8+ cd8+ cd8+ cd556+ cd8+ cd56+ clty clant+ cd8+ cd56+ cl+ cl+ cl+ cd556+滑膜炎。在体内和体外，这种CD8+ CD28-CD56+ TS细胞在滑膜成纤维细胞和其他滑膜APC上下调了共刺激分子CD86的表达。在这里，我们假设CD8+ CD28-CD56+ T细胞在RA的滑膜病变中通过Tolerizinq APC诱导CD4 T细胞的反应性。导致长期抑制这种疾病。特定的目标1旨在确定CD8+ CD28-CD56+ TS细胞通过这种分子机制调节APC诱导CD4 T细胞无反应性。特定的目标2将检查条件APC如何与CD4 T细胞相互作用，是否诱导成熟的免疫突触以及CD4 T细胞中的跨膜信号传导事件与正常激活不同。特别是，我们将检查此类CD4 T细胞是否具有在特定目的3中具有增强蛋白质信号蛋白的蛋白水解降解的厌食T细胞的特征，我们建议我们寻求将免疫抑制能力传递到CD8+ CD28-CD56+ T细胞上的关键分子和途径，包括有关CD56 Molecules of CD56 Molecule of CD56 Molecule ytry of CD28-CD56+ T细胞的研究。在特定的目标4中，我们将探讨这些专业的CD T细胞在预测疾病病程和预期伴随RA早期患者的疾病病程和结果方面是否具有价值作为生物标志物。相关性：类风湿关节炎是一种由免疫系统介导的残酷疾病。它可以治疗但不能治愈，对于受影响的个人和社会来说是昂贵的。免疫系统具有自然抑制免疫介导的炎症的细胞。该提案的目的是了解这种抗炎淋巴细胞的功能以及如何将其作为RA中的新型治疗试剂利用。