Biomarkers for assessing the immune state in rheumatoid arthritis and their application in a cellular therapy clinical trial

用于评估类风湿关节炎免疫状态的生物标志物及其在细胞治疗临床试验中的应用

• 批准号: 2884770
• 金额: --
• 依托单位: Newcastle University
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2884770
• 关键词: Biomarkers; assessing; immune; state; rheumatoid

BackgroundRheumatoid arthritis (RA) is caused by a loss of immune tolerance to self. Current clinical biomarkers assess inflammation but, as we treat earlier to prevent or cure disease, it will be increasingly important to assess the immune 'state'. For example, we have developed a novel therapeutic approach with tolerogenic dendritic cells (tolDC) that switch pathogenic self-reactive T-cells into regulatory/anergic T-cells. Our phase I clinical trial showed this therapy to be safe, and our forthcoming trial will compare different administration routes for efficacy. In order to demonstrate appropriate pharmacodynamic effects of tolDC, we will develop assays that assess the immune state, particularly the functional capabilities of autoreactive T-cells. Such surrogate outcome measures are the only way to provide true 'proof of concept' for such treatments.Objectives1) to validate existing and novel immunomonitoring tools for the characterisation of autoreactive T-cells in clinical samples from RA patients2) to apply these tools to probe changes in autoreactive-T-cells with tolDC treatment3) To define biomarkers for T-cell tolerance4) To extrapolate our findings to other clinical RA scenariosNoveltyThe novelty lies in combining state-of-the-art techniques to enrich autoreactive T-cells (including the use of HLA/peptide tetramers) and analysing those cells at single cell level, ultimately studying T-cells from our forthcoming tolDC clinical trial to demonstrate therapeutic immune modulation. TimelinessA number of antigen-specific tolerogenic therapies for autoimmune diseases are currently under development, for treatment and prevention. These include cell-based (e.g. tolDC) as well as nanoparticle-based strategies. However, suitable pharmacodynamic biomarkers are currently lacking, but will be essential outcome measures in clinical trials to demonstrate immune modulation.Experimental approachThe student will validate established techniques (multi-colour flow cytometry, ELISPOT, in vitro proliferation assay, single cell sequencing) alongside techniques we have developed to enrich autoreactive T-cells (HLA/peptide tetramers, activation-induced marker (AIM) assay) for use as immunomonitoring tools for clinical samples. These assays will then be applied to samples from the tolDC trial which include peripheral blood mononuclear cells, as well as lymph node aspirates, taken before and after tolDC administration. As a contingency, these novel tools can also be applied to probe the phenotype and function of autoreactive T-cells in other relevant scenarios, for example, from RA patients as they enter remission with standard-of-care treatment such as methotrexate, providing invaluable new insights into immune mechanisms of disease and their modulation by treatment.

背景风湿性关节炎（Rheumatoid arthritis，RA）是由于机体对自身免疫耐受的丧失而引起的一种疾病.目前的临床生物标志物评估炎症，但随着我们更早地治疗以预防或治愈疾病，评估免疫“状态”将变得越来越重要。例如，我们已经开发了一种新的治疗方法，其具有致耐受性树突细胞（tolDC），其将致病性自身反应性T细胞转换为调节性/无反应性T细胞。我们的I期临床试验表明这种疗法是安全的，我们即将进行的试验将比较不同的给药途径的疗效。为了证明tolDC的适当药效学作用，我们将开发评估免疫状态，特别是自身反应性T细胞的功能能力的测定法。目的1）验证现有的和新的免疫监测工具，用于表征RA患者临床样本中的自身反应性T细胞2）应用这些工具来探测tolDC治疗后自身反应性T细胞的变化3）定义T细胞耐受性的生物标志物4）将我们的发现外推到其他临床RA疾病新颖性新奇在于结合最先进的技术来富集自身反应性T细胞（包括使用HLA/肽四聚体）并在单细胞水平分析那些细胞，最终研究来自我们即将进行的tolDC临床试验的T细胞以证明治疗性免疫调节。及时性目前正在开发许多用于治疗和预防自身免疫性疾病的抗原特异性致耐受性疗法。这些包括基于细胞的策略（例如tolDC）以及基于纳米颗粒的策略。然而，目前缺乏合适的药效学生物标志物，但在临床试验中将是证明免疫调节的基本结果指标。（多色流式细胞术，ELISPOT，体外增殖测定，单细胞测序）以及我们开发的富集自身反应性T细胞的技术（HLA/肽四聚体，活化诱导标记（AIM）测定）用作临床样品的免疫监测工具。然后将这些测定应用于来自tolDC试验的样品，其包括在tolDC施用之前和之后采集的外周血单核细胞以及淋巴结抽吸物。作为一种应急措施，这些新工具也可以应用于探测其他相关情况下自身反应性T细胞的表型和功能，例如，当RA患者进入标准护理治疗（如甲氨蝶呤）缓解期时，为疾病的免疫机制及其治疗调节提供了宝贵的新见解。