CD8 T Cells in Rheumatoid Arthritis

尽管在抗细胞因子治疗方面取得了进展，但类风湿关节炎(RA)的治疗仍然需要 持续和积极的免疫抑制，有严重副作用的风险。这份提案是专门设计的 CD8+CD28~CD56+T抑制细胞抑制类风湿滑膜炎的机制探讨 以及它们如何发展成为治疗这种致残性疾病的新的过继免疫疗法 利用人类滑膜-结节-SCID嵌合体的临床前模型，我们已经确定了采用 转移CD8+CD28~CD56+T细胞克隆作为抑制滑膜炎症的有效手段。体内和体外 CD8+CD28“CD56+ts细胞下调共刺激分子CD86的表达 滑膜成纤维细胞和其他滑膜APC。这里我们假设CD8*CD28“CD56+T细胞诱导 类风湿关节炎滑膜病变中耐受性APC对CD4T细胞的无反应性导致长期的 对疾病的抑制。特定目标1旨在确定通过其 CD8+CD28~CD56+TS细胞调节APC诱导CD4T细胞无应答。特定目标2将 检查有条件的APC如何与CD4T细胞相互作用，成熟的免疫突触是否 以及CD4T细胞的跨膜信号事件与正常激活有何不同。在……里面 特别是，我们将检查这种CD4T细胞是否具有增强的无能T细胞的特征 特定目的中特定信号蛋白的蛋白降解3我们建议寻找关键的 CD8+CD28~CD56+T细胞免疫抑制能力的分子和途径， 包括对CD56分子本身作用的研究。在具体目标4中，我们将探讨这些 特化CDS T细胞作为生物标志物在预测疾病进程和预后方面具有前瞻性价值 跟踪观察早期类风湿关节炎患者。 相关：类风湿性关节炎是一种由免疫系统调节的致残性疾病。它可以是 治疗但没有治愈，对受影响的个人和社会来说代价高昂。免疫系统拥有 天然抑制免疫介导性炎症的细胞。这项建议的目标是了解如何 这种抗炎淋巴细胞的功能及其如何被用作新的治疗试剂 在RA。

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.