Grant: Operating Grant

The innate immune system is the first line of defence our bodies have against many infections and cancers. The innate immune system responds quickly, and its' classical job is to destroy infected or cancerous cells. More recently it has become apparent that the innate immune system may also play a significant role in regulating inflammation and the development of autoimmune diseases. Natural killer (NK) cells are an important component of the innate immune system and they are enriched within the normal liver. NK cells accumulate significantly within the liver during activation of the hepatic innate immune response, which often occurs in the setting of liver inflammation and liver autoimmunity. Although we know that NK cells are rapidly recruited to, and activated within the liver in response to many pathological insults, the mechanism driving their recruitment and accumulation within the liver during an innate immune response is poorly understood. Furthermore, it is becoming increasing clear that different types of NK cells exist, and some of these NK cell types may actually suppress liver inflammation and help the liver recover from damage which has occurred in response to an inflammatory insult. Therefore, the series of experiments outlined in this proposal will help us to establish a better understanding of the mechanisms which lead to the hepatic accumulation and activation of NK cells, as well as determine the regulatory roles played by NK cells in suppressing the hepatic innate immune response. This work may lead to the development of novel therapeutic strategies, involving the manipulation of hepatic NK cell numbers or subtypes, for the treatment of autoimmune and inflammatory liver diseases. Moreover, these findings may have broader implications for therapeutic approaches to autoimmune diseases in general.