Metabolic regulation of hepatic immunopathology by myeloid-derived suppressor cells

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Around one third of the world's population are estimated to have been exposed to hepatitis B virus (HBV) and at least 350 million people remain chronically infected. The resulting liver diseases include cirrhosis and liver cancer and are responsible for more than a million deaths every year. Existing therapies rarely achieve a cure. Patients are therefore consigned to long-term treatment, which remains unaffordable for many of the countries where the infection is most prevalent and carries risks of viral resistance and toxicity. Liver cancer is the third commonest cause of cancer-related deaths and treatments for it remain very limited. Our work is focused on understanding how to boost the body's natural immunity in order to achieve control of HBV and complications like liver cancer. We think that this should be achievable since many adults who get infected with HBV, naturally develop an immune response that controls it successfully for the rest of their lives. It is well known that T cells are critical for controlling viruses like HBV and that their numbers and function are drastically impaired in patients with chronic infection. We have found that one reason their T cells don't expand and work properly is that they are being starved of key nutrients like arginine. Our new findings reveal that another specialised immune cell type called "myeloid-derived suppressor cells" deprives T cells of nutrients and thereby stunts their responsiveness. These suppressor cells help to damp-down immune responses in the liver to stop them damaging this vital organ but in doing so, impair the control of pathogens like HBV. We now propose to define this process more comprehensively and investigate whether it can be manipulated to treat liver infections and other conditions such as tumours. A thorough understanding of the pathways and mechanisms involved will allow us to tailor therapies that can specifically target myeloid-derived suppressor cells or reverse the defects in "starved" T cells. This approach will be tested in the lab using cells extracted from the blood and liver of patients, in special 3D liver culture systems and in a new model of HBV infection. All samples are taken with fully informed consent and ethical board approval. Liver samples are only taken when there is surplus tissue left from procedures required for diagnosis or treatment.Our results will not only help with the development of better treatments for HBV and liver cancer, they will also enhance our understanding of how the liver suppresses immune responses. Our findings could therefore be applied to the treatment of other infections that target the liver like malaria and could conversely be harnessed to prevent rejection of liver transplants or to treat autoimmune liver disease.