Defining The Macrophage-Regulatory T Cell Axis That Promotes Fibrosis Resolution in the Liver

几乎所有的长期肝病，包括先天性代谢错误和免疫系统通过与糖尿病相关的代谢疾病攻击肝脏的疾病，都会导致肝脏瘢痕形成（称为纤维化），最终导致晚期瘢痕形成（称为肝硬化）。因此，肝脏疤痕现在是英国和西方世界常见的死亡原因。事实上，据估计，在西方，高达45%的死亡是直接或间接由组织瘢痕造成的，包括发生在肝脏的瘢痕。以前认为是不可逆的，我们的实验室已经证明，肝脏内的疤痕是动态的，在某些情况下，很容易分解，恢复到更正常的肝脏结构和更正常的肝功能。这种变化的关键是一种叫做巨噬细胞的细胞。尽管多年来人们一直认为巨噬细胞会促进炎症和疤痕的形成，但最近我们和其他人已经证明，巨噬细胞通过产生降解疤痕的化学物质，对疤痕组织的分解也至关重要。如果我们能够利用这种巨噬细胞的功能，我们将找到一种新的治疗方法来治疗肝脏和潜在的组织疤痕。这个应用程序描述了一个工作程序，以进一步了解是什么驱使巨噬细胞成为疤痕降解，因此作为一种治疗有价值。我们将研究巨噬细胞与另一种关键免疫细胞类型-调节性t细胞的相互作用，这可能在终止炎症和创造疤痕消退的条件中很重要。这项工作特别令人兴奋，因为我们将第一次看到细胞和分子的“开关”，它将炎症损伤过程转变为重塑和恢复正常功能的过程。我们对这种转换知之甚少，但通过拼凑分子机制，我们可能会打开新疗法的大门，不仅适用于疤痕，还适用于其他炎症突出且具有破坏性的疾病过程。最后，我们将研究巨噬细胞内的信号轴，已经有许可的药物，可以通过操纵来实现我们想要的工具，疤痕降解巨噬细胞。如果我们能够证明现有的药物（目前用于替代适应症）可以驱动巨噬细胞降解疤痕，那么这些药物可以迅速进入临床试验，因为它们的作用和副作用的重要评估已经知道，被定义为安全的，因此这些药物可以完全获得许可。

Virtually all long term liver disease, including inborn errors of metabolism and diseases where the immune system attacks the liver through metabolic diseases associated with diabetes, result in scarring of the liver (termed fibrosis) and ultimately advanced scarring (termed cirrhosis). As a result liver scarring is now a common cause of death in the UK and the western world. Indeed, it has been estimated that up to 45% of deaths in the west are the result either directly or indirectly of tissue scarring, including that which occurs in the liver. Previously believed to be irreversible, our laboratory has demonstrated that the scar within the liver is dynamic and, in certain circumstances, is susceptible to break down with a return of a more normal liver architecture and more normal liver function. Critical to this change is a cell called the macrophage. Although the macrophage has been known to promote inflammation and to drive the development of scarring for many years, recently we and others have demonstrated that it is also critical to the breakdown of scar tissue by producing the chemicals which degrade the scar. If we could harness this macrophage function, we would have identified a novel therapeutic approach to the treatment of liver and potentially tissue scarring generically. This application describes a programme of work to further understand what drives the macrophage to become scar degrading and therefore valuable as a therapy. We will study the interaction of the macrophage with another key immune cell type -the regulatory T-cells, which are likely to be important in terminating inflammation and creating the conditions in which resolution of scarring can occur. This work is particularly exciting as, for the first time we will be looking at the cell and molecular "switch" which changes an inflammatory damaging process to one in which remodelling and a return of normal function can take place. We know remarkably little about this switch and yet by piecing together the molecular mechanisms we may open the door to new therapies applicable not just to scarring, but to other disease processes in which inflammation is prominent and damaging. Finally, we will look at a signalling axis within the macrophage for which there are already licensed drugs and which may be amenable to manipulation to achieve our desired tool, the scar degrading macrophage. If we are able to show that existing drugs (currently used for an alternative indication) can drive the macrophages to degrade scars, then these drugs could rapidly come to clinical trials as the important asessments of their effects and side effects are already known, defined as safe and in consequence the drugs are fully licensed.