Dissecting the development and localisation of protective IL-10-secreting T cells in a model of hepatic immunopathology

人类的许多慢性疾病，包括1型糖尿病、肠易激综合征和酒精性肝硬变，都是由于身体脆弱器官出现不适当和过度的炎症。许多与感染相关的病理也是由于宿主自身免疫系统的过度激活。与炎症相关的病理也是伴随动物和牲畜物种健康状况不佳和生产力丧失的常见原因，对动物福利和粮食安全有影响。人体自身免疫系统引起的器官和组织损伤被称为免疫病理学，通常是由于免疫细胞(白细胞)在炎症器官内的聚集和激活。很明显，在我们开发更好的治疗方法来改善免疫病理学之前，我们需要更好地了解“健康的”炎症反应是如何受到调节的，以及为什么这些保护性的调节反应有时会失败。肝脏的炎症会导致急性肝功能衰竭，如果是慢性的，会导致肝硬变，最终导致肝功能衰竭。肝功能衰竭的常见原因包括感染(如肝炎病毒感染)和酗酒，以及自发性疾病和癌症。我们的目标是在急性肝脏免疫病理的小鼠模型中检查保护性(调节性)免疫反应的发展。我们将专注于产生可溶性介质白介素10(IL-10)的一种特殊的白细胞(称为CD4+T细胞)。越来越清楚的是，产生IL-10的CD4+T细胞对控制包括肝脏在内的许多不同器官的炎症非常重要，但目前我们不知道这些细胞在哪里发育，它们是从哪些细胞发育起来的，是什么信号导致它们分化，或者它们是如何在发炎的器官中积累的。为了回答这些问题，我们将产生一个小鼠群体，在其中导致炎症的细胞(效应细胞)产生黄色荧光蛋白，而分泌IL-10的细胞产生绿色荧光蛋白，这样我们就可以识别不同类型的细胞，因为它们在肝病的发展过程中分化和迁移到不同的器官，所以我们可以观察当我们使用各种实验方法诱导或阻止它们的发展时细胞群体的变化。这项工作的结果将揭示我们如何诱导或抑制产生IL-10的细胞的发展，以及我们如何增强或减少它们在特定器官中的积聚，以防止病理。这应该有助于开发新的药物来改善肝脏和其他器官的免疫病理学。

Many chronic diseases in humans, including type-1 diabetes, irritable bowel syndrome and alcohol-induced liver cirrhosis are due to the development of inappropriate and excessive inflammation in vulnerable organs of the body. Much of the pathology associated with infection is also due to over-activation of the host's own immune system. Inflammation-associated pathology is also a common cause of ill health and loss of productivity in companion animal and livestock species, with implications for animal welfare and food security. Organ and tissue damage caused by the body's own immune system is called immunopathology and is, in general, due to accumulation and activation of immune cells (leukocytes) within the inflamed organ. It is clear that before we can develop better therapies to ameliorate immunopathology, we need a much better understanding of how 'healthy' inflammatory responses are regulated and why these protective regulatory responses sometimes fail. Inflammation of the liver can lead to acute liver failure or, if chronic, to cirrhosis and eventually, liver failure. Common causes of liver failure include infection (e.g. hepatitis virus infections) and alcohol abuse, as well as automimune diseases and cancer. We aim to examine the development of protective (regulatory) immune responses in a mouse model of acute liver immunopathology. We will focus on a specific population of leukocytes (called CD4+ T cells) that produce the soluble mediator, interleukin-10 (IL-10). It is becoming clear that IL-10 producing CD4+ T cells are important for controlling inflammation in many different organs, including the liver but, at present, we do not know where these cells develop, which cells they develop from, what the signals are that cause them to differentiate or how they accumulate in inflamed organs. To answer these questions we will generate a colony of mice in which the cells that cause the inflammation (effector cells) produce a yellow fluorescent protein and the IL-10-secreting cells produce a green fluorescent protein, so that we can identify the different cell types as they differentiate and migrate to different organs during the development of liver disease and so that we can observe the changes in the cell populations when we use various experimental approaches to either induce or block their development. The results of this work will reveal how we can induce, or inhibit, the development of IL-10 producing cells and how we can enhance or reduce their accumulation in particular organs in order to prevent pathology. This should assist in the development of new drugs to ameliorate immunopathology in the liver and in other organs.