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

背景：免疫介导的炎症性疾病（IMIDs），如类风湿关节炎（RA）和溃疡性结肠炎（UC），其特征是异常的免疫反应导致慢性炎症和器官损伤。他们影响了西方5-7%的人口，而且这个数字还在上升。虽然有有效的治疗方法，但药物对几乎一半接受治疗的患者无效，而且这些疾病无法治愈。IMIDs是家族遗传的，在一个器官（如肠道）患病的人通常会在另一个器官（如关节或皮肤，甚至眼睛）患病。发生这种情况的原因尚不清楚，但使用一种名为PD1拮抗剂的药物治疗的患者所产生的副作用类型的相似性，为驱动组织趋向性的机制（即哪些器官受到哪些疾病的影响）提供了诱人的线索。PD-1是调节炎症的一个核心分子。程序性细胞死亡蛋白1 （PD-1）是一种免疫检查点抑制剂，存在于免疫细胞（T细胞和B细胞）上，激活后抑制炎症，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PARIS试验中，我们正在测试PD-1激动剂对UC、RA和干燥综合征的影响。然而，在PARIS试验的设计中有几个问题无法解决。例如，PD-1治疗的早期直接效应无法在临床试验中确定，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PD-1项目将克服这一限制，并为PD-1治疗的作用机制提供补充见解。目的和目标：本研究的目的是绘制PD-1治疗对UC和RA的直接影响。新技术的出现，使得完整的组织，或单个细胞和炎症分子，可以在实验皿中研究，使用从病人的肠道和关节中取出的活组织切片。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IMIDs中的PD-1生物学，我们将比较激活PD-1和抑制PD-1的效果。这些测试将扩展到组织水平，比较PD-1治疗在肠道和关节炎症组织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，并告知治疗策略以最大限度地减少可能的不良反应。像PD-1拮抗剂这样的免疫疗法已经彻底改变了肿瘤治疗，但在一些患者中会引起肠道或关节炎症等不良事件。PD-1在抵抗感染和过敏的免疫耐受中也很重要。该研究的结果将为PD-1治疗方法的个性化定制提供必要的见解。该项目不仅将有利于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.