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

背景资料：免疫介导的炎性疾病（IMID）如类风湿性关节炎（RA）和溃疡性结肠炎（UC）的特征在于导致慢性炎症和器官损伤的异常免疫应答。他们影响了5-7%的西方人口，而且人数还在上升。虽然有有效的治疗方法，但药物在接受治疗的患者中几乎有一半失去了效果，并且这些疾病无法治愈。IMID在家庭中传播，一个器官（如肠道）疾病的人通常会在另一个器官（如关节或皮肤，甚至眼睛）患病。为什么会发生这种情况尚不清楚，但使用有助于“治愈”癌症的药物（称为PD 1拮抗剂）治疗的患者的副作用类型相似，这为驱动组织向性的机制（即哪些器官受到哪些疾病的影响）提供了诱人的线索。程序性细胞死亡蛋白1（PD-1）是存在于免疫细胞（T和B细胞）上的免疫检查点抑制剂，其在活化时抑制炎症以促进免疫耐受。PD-1的失调被认为会促进UC和RA的炎症，因此是一个潜在的治疗靶点。在我参与的2期巴黎试验中，我们正在测试PD-1激动剂对UC、RA和干燥综合征的作用。例如，PD-1治疗的早期直接效应在本临床试验中无法确定，因为治疗前后的时间间隔延长（3个月），为间接效应的发生提供了空间。拟议的DPhil项目将克服这一限制，并提供PD-1 therapeutic.Aims和Objectives的作用机制的补充见解：本奖学金的目的是映射PD-1治疗在UC和RA的直接影响。新技术正在出现，允许完整的组织，或单个细胞和炎症分子在实验皿中进行研究，使用从患者肠道和关节中取出的活组织检查。我们将使用这些来确定PD-1治疗直接导致的早期细胞和分子改变。为了全面了解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治疗在肠道和关节的炎症和非炎症组织中的效果。潜在的应用和益处：潜在的益处包括洞察与PD-1治疗反应和无反应相关的早期机制活动，并为治疗策略提供信息，以最大限度地减少可能的不良反应。PD-1拮抗剂等免疫疗法彻底改变了肿瘤治疗，但在某些患者中会导致肠道或关节炎症等不良事件。PD-1在抗感染和过敏的免疫耐受中也很重要。这项研究的结果将提供针对个人环境定制PD-1治疗方法所需的见解。该项目不仅有利于IMDI的研究，还将扩展到癌症治疗，感染和过敏的研究。

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.