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

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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.