Tuesday 17 June 2014
The liver is the only organ in the body that can modify our immune response. This, paradoxically, leaves it open to violent immune attack.
Researchers at Sydney’s Centenary Institute and the University of Sydney have now discovered the means by which this happens. In the process they may have opened a pathway towards improving treatment of chronic hepatitis.
The key is in the way the immune system’s T cells operate in the liver.
The researchers found that when the liver T cells encounter a small number of cells making a foreign protein, they function in the normal way—stimulating the production of cells to kill off the source of the protein.
But when they encounter large amounts of foreign protein beyond a certain threshold, the T cells are overwhelmed and fail. This weakening of the defence system is the Achilles heel of the liver, making it more susceptible to invasion by viruses that replicate rapidly and produce large amounts of protein.
“That’s what we think happens when a virus such as hepatitis B or C invades the liver,” says Dr Patrick Bertolino, co-head with Dr David Bowen of Centenary’s Liver Immunology Research Group. “The viruses multiply very fast, spreading to many liver cells, and in doing so they force a high proportion of them to make huge amounts of protein.”
If this process could be slowed or delayed on initial infection, the researchers believe that the immune system would have a much better chance of clearing the virus – as it already does in about 30 per cent of cases of hepatitis C.
Their work, which was undertaken in collaboration with the Children’s Medical Research Institute at the Westmead Hospital, has just been published online in the Proceedings of the National Academy of Sciences.
In earlier studies, the Centenary research team found that the liver is the only place in the body outside of the lymph nodes with the capacity to activate T cells. But, in contrast to the lymph nodes, the T cells activated by the liver do not function efficiently and most of them are eliminated. By this means, the liver can damp down immune system activity.
Bertolino says the next step in this work is to see if T cells, exhausted by high concentrations of viral protein, can be rescued in some way. The group has already shown in mice that it is possible to revive such overwhelmed cells within the first week after they have encountered a high amount of protein in the liver.
In 2011 about 209,000 people were living with Hepatitis B infection in Australia resulting in about 382 deaths, according to a 2012 report from the Kirby Institute at the University of New South Wales. The equivalent figures for Hepatitis C are 304,000 resulting in about 380 deaths.
For interviews and more information:
- Toni Stevens, Science in Public, on 0401 763 130 or firstname.lastname@example.org
- Patrick Bertolino, Head, Liver Immunology Research Group, Centenary Institute on 0402 850 402 or email@example.com
- David Bowen,Head, Liver Immunology Research Group, Centenary Institute on 0421 442 383 or firstname.lastname@example.org
- Jill Atherton, Centenary Institute on 0466 166 878 or email@example.com
CD8 T-cell responses to liver-expressed antigens range from deletional tolerance to full effector differentiation resulting in overt hepatotoxicity. The reasons for these heterogeneous outcomes are not well understood. To identify factors that govern the fate of CD8 T cells activated by hepatocyte-expressed antigen, we exploited recombinant adeno-associated viral vectors that enabled us to vary potential parameters determining these outcomes in vivo. Our findings reveal a threshold of antigen expression within the liver as the dominant factor determining T-cell fate, irrespective of T-cell receptor affinity or antigen cross-presentation. Thus, when a low percentage of hepatocytes expressed cognate antigen, high-affinity T cells developed and maintained effector function, whereas, at a high percentage, they became functionally exhausted and silenced. Exhaustion was not irreversibly determined by initial activation, but was maintained by high intrahepatic antigen load during the early phase of the response; cytolytic function was restored when T cells primed under high antigen load conditions were transferred into an environment of low-level antigen expression. Our study reveals a hierarchy of factors dictating the fate of CD8 T cells during hepatic immune responses, and provides an explanation for the different immune outcomes observed in a variety of immune-mediated liver pathologic conditions.
About Patrick Bertolino and David Bowen
Co-Heads, Liver Immunology Group, Centenary Institute
Dr Patrick Bertolino
Dr Bertolino is internationally recognised as a world-leading expert in Liver Immunology and has made major contributions related the ability of the liver to induce tolerance in transplantation, and chronic HCV infection. He has demonstrated that naïve T cells can be activated directly in the liver.
This fundamental finding overturned the conventional belief that primary T-cell activation is unique to lymphoid tissues. His group investigates the consequences of these interactions to define the parameters that determine intrahepatic immunity/tolerance and chronic hepatitis. Dr Bertolino has served on major scientific committees in Australia.
Dr David Bowen
David is a clinician scientist at Centenary Institute, who also practices as a clinical hepatologist at the AW Morrow Gastroenterology and Liver Centre and the Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital.
Dr Bowen’s main clinical and research interests centre upon liver transplantation, where his research work in collaboration with Dr Bertolino focuses on understanding how to improve acceptance of liver transplants without the need for immunosuppression with its associated significant side effects. In addition, his work also concentrates upon understanding hepatitis C related liver disease post-liver transplantation. Dr Bowen’s work in this area focuses on understanding how recurrent disease occurs, aiming to develop new strategies to improve outcomes for these individuals.
About the Liver Immunology Research Group
The research of this group is focused on the liver, an organ with unique tolerogenic properties. In many species, liver transplants are spontaneously accepted across a complete MHC mismatch and some viral infections, such as the one by the Hepatitis C virus, become chronic suggesting that the virus exploit this liver property to persist in the host.
The mechanisms involved in these processes remain unknown. The broad aims of our group are to understand the interactions between T lymphocytes and hepatic cells, the parameters that determine the balance between tolerance and immunity in the liver as well as those leading to chronic hepatitis.
We are particularly interested in dissecting complex mechanisms of liver-induced tolerance of CD8+ T cells, which are responsible for graft rejection and virus clearance.
About the Centenary Institute
The Centenary Institute is an independent leader in medical research seeking improved treatments and cures for cancer, cardiovascular and infectious diseases. We are working to discover new prevention, early diagnosis and treatment options to enable each generation to live longer, healthier lives than the one before. Centenary’s affiliation with the RPA Hospital and the University of Sydney means that our discoveries can be quickly applied to the fight against disease in the clinic.