Research within the Liver Immunology Program aims to advance our understanding of the mechanisms by which the liver induces immunological tolerance. In addition, we seek to characterise the key determinants of effective immune responses in this organ, to facilitate enhancement of immunity in circumstances where this is advantageous. Our research is highly relevant to a range of clinically important settings including transplantation, infections such as viral hepatitis and malaria, and gene therapy.
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.
Patrick Bertolino, Head of Program
Phone: (02) 9565 6186
Patrick Bertolino is a Faculty member at the Centenary Institute (CI) where he leads the Liver Immunology Group. He is a leader in the field within Australia, and is considered one of the leading world experts in Liver Immunology. He trained as an immunologist in distinguished research institutes (WEHI, CI, Ecole Normale Supérieure de Lyon) where he worked with first class scientists including Jacques F.A.P Miller, recipient of the 2019 Lasker award for his discovery of T and B cells.
Associate Professor Bertolino’s research for the last 25 years has focused on understanding the parameters that determine the balance between tolerance and immunity in the liver, an organ known for its ability to induce tolerance. More recently, he has extended his research interest to liver macrophages. By developing and establishing unique transgenic mouse models and tools to analyse the liver immune response, he has built an original and productive research program that is unmatched in this discipline. The pioneering concepts contributed by his research program have shaped the nascent liver immunology discipline and promoted his leading international reputation in this discipline.
Funding: A/Prof Bertolino has had consistent success in securing competitive research grants as a main investigator, illustrating his independence and leadership: He has held continuous NHMRC research funding since 2000: 2 Program Grants (PI 2005-9, CI 2010-4), and 9 project grants: 6 as CIA (1 current awarded in 2018) and 3 as co-CI. He has also obtained highly competitive international funding (Roche Foundation). He was awarded an NHMRC SRF (2008-2014). Overall total funding brought by his competitive research grants is approximately $17.8 million, with ~$3.5 million as CIA. He has also participated as a PI or CI in many University Sydney NHMRC Major Equipment Grants.
Research Outputs: A/Prof Bertolino’s track record in reputable journals reflects his consistent productivity. He has published 95 manuscripts in total, with 54/95 published in the last 10 years. He is first/last author of 50/95 articles and 2nd/2nd last author in 10/95 articles, reflecting his intellectual input in these works. Reflecting the high quality of the research work under his leadership, he is senior author of many publications in top journals (including Immunity, J Clin Invest, PNAS, and Gastroenterology). The total number of citations for his papers reflect their high impact in the field, more than doubling in the last 5 years (5,128 citations in 2019 versus 2,159 2014). 16 articles have been cited>100 times and 28 more than 50 times.
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Dr David Bowen, Joint Head of Program
Phone: (02) 9565 6186
David Bowen is Associate Faculty at the Centenary Institute, where he co-leads the Liver Immunology Program with A/Prof Patrick Bertolino. He is also an Associate Professor at the Sydney Medical School, University of Sydney, where he has played a leading role in research education within the MD Research Program, and a Gastroenterologist and Hepatologist at The AW Morrow Gastroenterology and Liver Centre and Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital.
In addition to his involvement in the group’s studies of liver immunobiology in animal models, his research interests include analysis of liver-directed immune responses in the clinic, particularly in viral hepatitis and post-liver transplantation, seeking to translate the group’s findings into clinical applications.
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