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The role of the TIGIT immune checkpoint axis in susceptibility to infection in decompensated cirrhosis

TIGIT 免疫检查点轴在失代偿性肝硬化感染易感性中的作用

基本信息

批准号：
MR/X018385/1
负责人：
Joseph Delo
金额：
$ 35.53万
依托单位：
St George's, University of London
依托单位国家：
英国
项目类别：
Fellowship
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=MR%2FX018385%2F1
关键词：
role TIGIT immune checkpoint axis

项目摘要

One in ten people in the UK have liver disease and the progressive development of liver damage can lead ultimately to cirrhosis. Patients with cirrhosis can remain well for many years but a proportion will develop complications such as ascites (fluid in the abdomen), upper gastrointestinal bleeding, encephalopathy (a state of confusion), or jaundice. This is called decompensated cirrhosis and if this causes other organs in the body to fail then it is termed acute-on-chronic liver failure. One of the most profound consequences of decompensated cirrhosis and acute-on-chronic liver failure is that patients are highly susceptible to infections. Infections in these patients have a very poor prognosis with a high mortality, even with antibiotic treatment. Therefore it is important to try to understand why these patients are more susceptible to infections in the first place so we can develop new treatments. An interesting observation in patients with decompensated cirrhosis is that although their immune system is highly activated, the immune cells do not fight infections well. Our theory is that this, in part, is because the cells have a higher level of a type of molecule called immune checkpoints. Immune checkpoints act as the "brake" on the immune system and while they can be helpful to prevent damage from an over-active immune system, too much can hamper the immune system's ability to fight diseases. Cancer cells have higher levels of immune checkpoints and a new type of cancer treatment ("immunotherapy") works by blocking immune checkpoints.We are interested in a particular group of immune checkpoints collectively called the "TIGIT axis" on T cells, a key type of immune cell that fights infections and coordinates immune responses. These immune checkpoints have been shown to impair T cell function against cancer and chronic viral infections (like HIV). To investigate our theory that they are also involved in poor T cell functions in decompensated liver disease, we will look at the levels of the TIGIT axis immune checkpoints on T cells that we find in blood, the liver, and in ascites (the fluid that collects in the abdomen). We will then go on to investigate if having more of these immune checkpoints makes the T cells less effective, and if we can improve this by blocking the immune checkpoints.We will recruit patients from outpatient clinics or who are admitted to hospital. With their consent we will collect samples of blood and ascites, and collect data about their medical history and medication. If they have a liver biopsy to diagnose their condition, then we will ask to use part of the sample. We will follow them up for up to 1 years after they join the study.Overall, the intended benefit is that if we can identify a particular immune checkpoint then it could be a target for new medication to reset the immune system in patients with decompensated cirrhosis and reduce their susceptibility to infection.

在英国，十分之一的人患有肝脏疾病，肝脏损伤的逐渐发展最终可能导致肝硬化。肝硬化患者可以保持多年的良好状态，但部分患者会出现并发症，如腹水（腹部液体），上消化道出血，脑病（混乱状态）或黄疸。这被称为失代偿性肝硬化，如果这导致身体其他器官衰竭，那么它被称为慢性急性肝功能衰竭。失代偿性肝硬化和慢加急性肝功能衰竭最严重的后果之一是患者极易感染。这些患者的感染预后非常差，即使使用抗生素治疗，死亡率也很高。因此，重要的是要了解为什么这些患者首先更容易感染，这样我们就可以开发新的治疗方法。失代偿期肝硬化患者的一个有趣的观察结果是，尽管他们的免疫系统高度激活，但免疫细胞不能很好地抵抗感染。我们的理论是，这在一定程度上是因为细胞具有更高水平的一种称为免疫检查点的分子。免疫检查点充当免疫系统的“刹车”，虽然它们有助于防止过度活跃的免疫系统造成的损害，但过多的检查点会阻碍免疫系统对抗疾病的能力。癌细胞具有更高水平的免疫检查点，一种新型的癌症治疗（“免疫疗法”）通过阻断免疫检查点发挥作用。我们对T细胞上的一组特定的免疫检查点感兴趣，这些免疫检查点统称为“TIGIT轴”，T细胞是一种关键类型的免疫细胞，可以对抗感染并协调免疫反应。这些免疫检查点已被证明会损害T细胞对抗癌症和慢性病毒感染（如HIV）的功能。为了研究我们的理论，即它们也参与失代偿性肝病中T细胞功能低下，我们将研究我们在血液，肝脏和腹水（收集在腹部的液体）中发现的T细胞上的TIGIT轴免疫检查点的水平。然后我们将继续研究这些免疫检查点是否会使T细胞的效率降低，以及我们是否可以通过阻断免疫检查点来改善这一点。我们将从门诊诊所或住院患者中招募患者。在他们的同意下，我们将收集血液和腹水样本，并收集有关他们的病史和药物的数据。如果他们有肝活检来诊断他们的病情，那么我们将要求使用部分样本。我们将在他们加入研究后对他们进行长达1年的随访。总体而言，预期的益处是，如果我们能够识别特定的免疫检查点，那么它可能成为新药物的目标，以重置失代偿性肝硬化患者的免疫系统，并降低他们对感染的易感性。