Liver Immunology Program
Unique immune properties of the liver
Through a process known as immune tolerance, the liver has the unique ability to dampen down immunity. This is reflected by the fact that long-term acceptance of a transplanted liver requires significantly lower doses of immunosuppressive medications that that required for other organs, and transplantation of a liver prevents the rejection of other organs transplanted from the same donor.
In up to 25% of individuals, immunosuppressive medication can eventually be ceased without the transplanted liver being rejected. While this property of “liver tolerance” is beneficial in transplantation, it can be detrimental during immune responses against liver tropic microbes such as viral hepatitis and malaria. The hepatitis B and hepatitis C viruses (HBV and HCV) are particularly thought capable of hijacking this liver property, to prevent their being eliminated by the host immune response, thus resulting in chronic infection.
The dramatic rise of liver diseases
Chronic liver disease affects millions of individuals worldwide, and arises from a wide variety of aetiologies. Damage to the liver can be associated with a wide variety of different factors, including viral infections, autoimmunity, alcohol, fat, and toxins. However, the inflammation that contributes to liver injury is often mediated by immune cells residing in the organ and those recruited to the site of inflammation. Over time, chronic injury leads to the accumulation of scar tissue, or fibrosis, eventually progressing to cirrhosis, with consequent liver failure or liver cancer.
Liver disease comprises a significant health burden to the community, and rates are currently soaring globally, fuelled by the epidemic progression of viral hepatitis and the rise of obesity, particularly in the West. Current solutions are inadequate: there is currently no vaccine for HCV and no cure for HBV. While many anti-fibrotic drugs have been studied, none are yet in clinical use. Patients with end-stage chronic liver diseases currently have only one available, but resource limited solution: liver transplantation. Due to a shortage of organ donors and cost, less than 10% of liver transplant needs are currently met. The fate of the 90% of individuals that do not receive a liver graft is eventually death. Transplant recipients are treated with immunosuppressive medications after surgery, and most will remain on this medication lifelong to prevent graft rejection. However, these medications are associated with significant side effects in the long term.
Aims and long-term objectives of the research
The research program of the Liver Immunology Group aims to gain novel insights into the relationship between the liver and the immune system. The ultimate goal of our work is to develop new treatments and strategies to prevent, slow down, or stop the progression of chronic liver disease, and improve the life of transplant patients by enhancing the survival of organ grafts using strategies that allow the minimal use of immunosuppressive agents.
The Liver Immunology Group uses unique transgenic mouse models, advanced imaging, and multiparameter flow cytometry technologies to dissect the mechanisms regulating the balance between tolerance and immunity in the liver, by determining how T cells interact with and are instructed by hepatic cells in healthy, diseased, and transplanted liver. The group also investigates the role of liver macrophages in maintaining homeostasis, and in regulating inflammation in clinically relevant liver diseases.
The group is internationally recognised for having made several key contributions to the field of liver immunology. These discoveries, published in pioneering landmark papers, have transformed the field and greatly advanced our knowledge of liver immune responses during infections and in liver transplantation. Although they did not initially conform with existing paradigms, these discoveries are now part of current models and referenced in many immunology textbooks. A selection of these discoveries is listed below:
- Uncovering an alternate liver-specific T cell activation pathway leading to tolerance. This seminal discovery overturned the prevailing paradigm that primary T cell activation is restricted to lymphoid tissues, and identified the site of initial T cell activation as a key determinant of intrahepatic immunity. This body of work shed light on previous clinical observations in hepatitis and transplantation, and inspired work leading to other key contributions to the field.
- Discovering a new mechanism of T cell tolerance mediated by T cell degradation inside hepatocyte lysosomes. This opened a new research area in T cell immunology, and attracted attention from both the scientific community and media. It inspired work in other fields; with this finding being cited in cancer studies as key evidence suggesting primary cell cannibalism may drive tumorigenesis.
- Demonstrating that the site of primary CD8 T cell activation and the level of antigen load are 2 key determinants of the outcome of the CD8 T cell response against antigens expressed in the liver.
- Characterising a new subset of memory CD8 T cells that do not recirculate, but play a key protective role in intrahepatic immunity against liver tropic pathogens (in collaboration with Professor Willam R Heath, the Peter Doherty Institute for Infection and Immunity). This work informed design of a novel candidate vaccine approach against malaria. Involving a strategy favouring effective CD8 T cell priming in secondary lymphoid organs, combined with induction of a low level of intrahepatic antigen expression to promote liver homing without the induction of tolerance, this technique elicited high numbers of liver resident memory CD8 T cells and effective protection against malaria in an animal model.
- Characterising a previous unidentified subset of macrophage distinct from Kupffer cells residing in the liver capsule.
The Liver Immunology Group uses unique transgenic mouse models, advanced imaging, and multiparameter flow cytometry technologies to dissect the mechanisms regulating the balance between tolerance and immunity in the liver, by determining how T cells interact with and are instructed by hepatic cells in healthy, diseased, and transplanted liver. The group also investigates the role of liver macrophages in maintaining homeostasis, and in regulating inflammation in clinically relevant liver diseases.
The group is internationally recognised for having made several key contributions to the field of liver immunology. These discoveries, published in pioneering landmark papers, have transformed the field and greatly advanced our knowledge of liver immune responses during infections and in liver transplantation. Although they did not initially conform with existing paradigms, these discoveries are now part of current models and referenced in many immunology textbooks. A selection of these discoveries is listed below:
- Uncovering an alternate liver-specific T cell activation pathway leading to tolerance. This seminal discovery overturned the prevailing paradigm that primary T cell activation is restricted to lymphoid tissues, and identified the site of initial T cell activation as a key determinant of intrahepatic immunity. This body of work shed light on previous clinical observations in hepatitis and transplantation, and inspired work leading to other key contributions to the field.
- Discovering a new mechanism of T cell tolerance mediated by T cell degradation inside hepatocyte lysosomes. This opened a new research area in T cell immunology, and attracted attention from both the scientific community and media. It inspired work in other fields; with this finding being cited in cancer studies as key evidence suggesting primary cell cannibalism may drive tumorigenesis.
- Demonstrating that the site of primary CD8 T cell activation and the level of antigen load are 2 key determinants of the outcome of the CD8 T cell response against antigens expressed in the liver.
- Characterising a new subset of memory CD8 T cells that do not recirculate, but play a key protective role in intrahepatic immunity against liver tropic pathogens (in collaboration with Professor Willam R Heath, the Peter Doherty Institute for Infection and Immunity). This work informed design of a novel candidate vaccine approach against malaria. Involving a strategy favouring effective CD8 T cell priming in secondary lymphoid organs, combined with induction of a low level of intrahepatic antigen expression to promote liver homing without the induction of tolerance, this technique elicited high numbers of liver resident memory CD8 T cells and effective protection against malaria in an animal model.
- Characterising a previous unidentified subset of macrophage distinct from Kupffer cells residing in the liver capsule.
