Tissue tropism of PD-1 therapy in ulcerative colitis and rheumatoid arthritis

PD-1治疗溃疡性结肠炎和类风湿性关节炎的组织向性

• 批准号: MR/Y009681/1
• 负责人: Tom Hosack
• 金额: $ 41.48万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY009681%2F1
• 关键词: Tissue; tropism; PD; therapy; ulcerative

Background: Immune-mediated inflammatory diseases (IMIDs) such as Rheumatoid Arthritis (RA) and ulcerative colitis (UC) are characterized by an aberrant immune response which leads to chronic inflammation and damage to organs. They affect 5-7% of the Western population with numbers rising. While there are effective treatments available, medications lose their effect in almost half of patients treated, and there is no cure for these diseases.IMIDs runs in families and people with disease in one organ such as the gut often get disease in another, such as the joints or skin, or even eyes. Why this happens is not clear but similarities in the types of side effects from patients treated with a drug that helps "cure" cancer called a PD1 antagonist, have given tantalizing clues as to the mechanisms that drive tissue tropism (i.e. which organs are affected by which diseases).One molecule central to moderating inflammation is PD-1. Programmed cell death protein 1 (PD-1) is an immune checkpoint inhibitor present on immune cells (T and B cells) which upon activation dampens inflammation to promote immune tolerance. Dysregulation of PD-1 is thought to promote inflammation in both UC and RA and is thus a potential therapeutic target In the Phase 2 PARIS trial I am part of, we are testing the effect of a PD-1 agonist across UC, RA and Sjogren's syndrome.However, there are several questions that cannot be addressed within the design of the PARIS trial. For example, the early direct effects of PD-1 therapy cannot be determined in this clinical trial setting, as the extended time interval between before and after therapy (3 months) gives room for indirect effects to take place. The proposed DPhil project will overcome this limitation and provide complementary insights on the mechanism of action of PD-1 therapy.Aims and Objectives:The aim of this fellowship is to map the direct effects of PD-1 therapy across UC and RA. New technologies are emerging which allow intact tissues, or individual cells and inflammatory molecules, to be studied in an experimental dish, using biopsies taken from patients' intestines and the joint. We will use these to determine the early cellular and molecular alterations that are a direct result of PD-1 therapy. To provide a complete insight into PD-1 biology in IMIDs, we will compare the effects of activating PD-1 with inhibiting PD-1. These tests will be extended to the tissue level, comparing effects of PD-1 therapies in inflamed and non-inflamed tissue of the intestine and joints.Potential Applications and Benefits:Potential benefits include insight into early mechanistic activities associated with therapeutic response and non-response to PD-1 therapy and inform therapeutic strategies to minimise possible adverse effects. Immunotherapies like PD-1 antagonists have revolutionized oncological management, but in some patients cause adverse events like gut or joint inflammation. PD-1 is also important in immune tolerance against infection and allergy. The findings form this fellowship will provide the insights required to tailor PD-1 therapeutic approaches to the individual setting. By this the project will not only benefit research into IMDIs, but also extend to research into cancer therapy, infections and allergies.

背景：免疫介导的炎症性疾病（IMID），例如类风湿关节炎（RA）和溃疡性结肠炎（UC）的特征在于异常的免疫反应，导致慢性炎症和对器官的损害。它们影响了5-7％的西方人口，人数增加。尽管有有效的治疗方法，但药物在几乎一半接受治疗的患者中失去了作用，并且无法治愈这些疾病。Imids在一个家人和一个器官中的疾病患者（例如肠道）中经常在另一个器官中疾病，例如关节或皮肤，甚至眼睛。为什么发生这种情况的原因尚不清楚，但是用药物治疗的患者的副作用类型的相似性，该药物有助于“治愈”称为PD1拮抗剂的癌症，给出了有关驱动组织向向性主义的机制的诱人线索（即，哪些器官受到哪些疾病的影响）。一种疾病的影响。一种是针对炎症炎症的中心分子。程序性细胞死亡蛋白1（PD-1）是免疫细胞（T和B细胞）上存在的免疫检查点抑制剂，激活后会抑制炎症以促进免疫耐受性。人们认为PD-1的失调被认为会促进UC和RA的炎症，因此在第二阶段巴黎试验中是一个潜在的治疗靶标，我们正在测试UC，RA和Sjogren综合征的PD-1激动剂的效果。但是，在Paris试验的设计中，在PARIS综合征的设计中无法解决几个问题。例如，在这种临床试验环境中无法确定PD-1治疗的早期直接影响，因为治疗前后的时间间隔（3个月）为间接效应提供了空间。拟议的DPHIL项目将克服这一限制，并就PD-1治疗的作用机理提供互补的见解。IAMS和目标：该研究金的目的是绘制跨UC和RA的PD-1治疗的直接影响。新技术正在启动，可以使用从患者的肠道和关节进行活检，在实验菜肴中研究完整的组织或单个细胞和炎症分子。我们将使用这些来确定PD-1治疗的直接结果的早期细胞和分子改变。为了完全了解IMID中的PD-1生物学，我们将比较激活PD-1与抑制PD-1的效果。这些测试将扩展到组织水平，比较PD-1疗法在肠和关节的发炎和非燃烧组织中的影响。潜在的应用和益处：潜在的好处包括对治疗性反应的早期机械活性的洞察力以及对PD-1治疗以及对PD-1疗法的无反应以及对治疗疗法的无反应，以最大程度地减少可能的不良影响。 PD-1拮抗剂等免疫疗法彻底改变了肿瘤学管理，但是在某些患者中，肠道或关节炎症等不良事件。 PD-1在免疫耐受性感染和过敏方面也很重要。该奖学金的发现形式将为各个环境量身定制PD-1治疗方法所需的见解。通过此，该项目不仅将受益于对IMDI的研究，而且还将扩展到对癌症治疗，感染和过敏的研究。