New hepatitis studies to aid search for new treatments

Insights into the biological processes underpinning both diseases could lead to improvements in diagnosis, treatment and disease management for patients.

Viral hepatitis is an infection that causes liver inflammation and damage. There are several different viruses that cause hepatitis, including hepatitis A, B, C, D and E.

Hepatitis A and E are typically acute infections where the body is able to fight the infection and the virus goes away. Hepatitis B, C and D are generally more severe. They are spread through contact with an infected person’s blood and bodily fluids, and can cause both acute and chronic conditions. Chronic hepatitis can lead to cirrhosis of the liver, liver failure, and liver cancer.

Viral hepatitis B and C affect 325 million people worldwide, causing 1.4 million deaths every year. Although hepatitis B is more common in southeast Asia and sub-Saharan Africa, it still affects around 180,000 people in the UK. Around 215,000 people have hepatitis C, making it the most common type of viral hepatitis in the UK.

Current and new viral hepatitis treatments can sometimes lead to a cure, but this is often hampered by medical cost, a high requirement for patient compliance, medical complications, and additional complications associated with the prospect of life-long antiviral therapy.

Autoimmune hepatitis (AIH) is a rare cause of long-term hepatitis in which the body’s immune system attacks and damages the liver. There are thought to be around 10,000 people living with autoimmune hepatitis in the UK, and although both men and women can develop the condition, it is more common in young women. It is not currently clear what causes AIH or whether anything can be done to prevent it.

Existing treatments for AIH aim to reduce inflammation by suppressing the immune system, but this can also reduce the immune system’s ability to fight infection. Current treatments do not provide a cure; they need to be taken life-long and, despite therapy, people with AIH can go on to develop liver cirrhosis, liver failure and the need for a liver transplant.

Due to inherent problems with existing treatments for both viral and autoimmune hepatitis, new approaches are urgently needed.

Four mid-career researchers were selected for funding, from Queen Mary University of London, Glasgow Caledonian University, and the University of Birmingham.

Angela Hind, Chief Executive of the Medical Research Foundation, said: “We hope these new studies will increase our understanding of viral and autoimmune hepatitis, and ultimately, we hope these insights will save lives.

“This new funding aligns with our broader aim to support outstanding scientists, by providing funding at a critical stage in their careers, and putting them on a trajectory to research independence, so that they can have long and fruitful careers in hepatitis research. All of which is crucial for changing people’s lives in the decades to come.”

The research into viral hepatitis has been made possible by gifts in Wills from Effie Millar Munro, Alfred Tartellin and Jenny Porley. Dr Hamish Innes’ research is also funded by a gift from Jeanie Bell. All of these supporters had an interest in tackling the problem of liver diseases through research.

Dr Zania Stamataki’s AIH project is funded by donations from Robert Colvile and his supporters. Robert launched a fundraising appeal following the tragic death of his wife Andrea.

Dr Palak Trivedi from the University of Birmingham will investigate whether immunotherapy could hold promise for controlling liver damage in patients with AIH.

“There is evidence that in people with AIH, the body’s protective mechanisms are duped and do not work properly. The exact disturbance is unclear, but we think there’s a reduced function of potentially protective immune cell types (called regulatory T cells, or ‘Treg’) and an increased number and function of cells that drive inflammation (effector T cells). The key question is: how do we restore the balance between protective cell types and the ones that drive inflammation?”

In his study, Dr Trivedi will investigate whether injections of Treg can control liver damage caused by the body’s immune system. Previous work from the Birmingham research group has shown that Treg can be taken from patients, enhanced in the lab, and safely returned by injection, with a quarter of the injected cells travelling back to the inflamed liver.

“The next step is to understand whether Treg still function as a protective cell type once they get to the liver, and whether they remain stable long enough to control tissue-damaging cell types.

“My project will take Treg from patients awaiting a liver transplant, then enhance and populate them in the lab. When patients undergo their liver transplant, we’ll inject Treg back into the damaged liver which has been removed during the operation. From a research perspective, studying the damaged liver in the lab - in real time - to examine the function of these cell types, is a world-first approach. It will offer vital clues for future research into whether Treg could benefit patients clinically.

“We want to take a targeted treatment approach, which homes in on the liver and gives the body the type of immune cells it needs to keep the fine balance of protective and inflammatory cells in check.”

Dr Trivedi’s work could then be used to identify and treat patients much earlier, and eventually be used to minimise the volume of medicines patients need, and prevent progression to liver failure.

Dr Zania Stamataki, also from the University of Birmingham, will investigate the impact of targeting a new biological phenomenon called enclysis in viral and AIH. This is important because liver diseases are on the rise, and death rates due to liver cancer are increasing worldwide.

In autoimmune disease, a misguided immune system recognises its own tissue as a foreign pathogen and launches a relentless attack to eliminate the threat (i.e. an overactive immune system). In viral liver disease, an ineffective immune system fails to clear the virus, which leads to persistent infection for life. Studies have shown that Treg cells can impact the progression of both disease processes. So how does the liver regulate the regulators (Treg cells)?

Dr Stamataki’s team have identified a new process that may answer this question. “We recently discovered that the main cells that make up 80 per cent of the liver, hepatocytes, actively engulf T-reg cells and destroy them. We called this new phenomenon enclysis, from the Greek word for enclosure, confinement and captivity. Indeed, we found increased enclysis in AIH compared to hepatitis B livers donated to research after transplantation. It is therefore possible that toggling enclysis may help improve both disease outcomes, and we have planned a series of experiments to test this hypothesis using human liver tissues.”

Researchers are exploring two clinical approaches aimed at restoring balance in the immune system: one where protective T-reg cells are isolated from AIH patients, expanded in the lab and injected back into patients, with the hope of dampening inflammation; and the other where immune cells are isolated from viral patients, activated and injected back into patients to fight the virus. Dr Stamataki’s study will focus on understanding how to improve and prolong the effectiveness of these immunotherapies for patient benefit.

Dr Hamish Innes from Glasgow Caledonian University will develop a new clinical prediction model which estimates the benefit of liver cancer screening for patients with liver cirrhosis, who have been cured of hepatitis C. With this model, clinicians will be able to identify those patients who will gain the most from screening in terms of increased life expectancy (and vice versa, those who are likely to benefit minimally or not at all). This is something that existing prediction models are not able to do.

Dr Innes said: “There are so many reasons why research in this area is important. One key issue is that there has been a huge increase in the number of patients with liver cirrhosis who have achieved a hepatitis C ‘cure’ - and we don't really understand right now which patients need to be screened for liver cancer and which, if any, do not. Also, liver cancer screening is currently performed in a very ad-hoc way in many clinics; improved prediction models could facilitate a more systematic and consistent approach to screening for all patients.

“We hope this project will improve survival rates, following a diagnosis of liver cancer, in patients with cirrhosis and a hepatitis C cure. The modelling framework we develop could also be adapted to liver cancer screening for patients with other forms of chronic liver disease, such as alcohol-related liver disease and non-alcoholic fatty liver disease.”

Dr Upkar Gill from Queen Mary University of London is investigating the immune and viral outcomes of treatment in patients with chronic hepatitis B, using a minimally invasive liver sampling technique.

Work from Dr Gill’s previous research groups showed that a subset of immune T and natural killer (NK) cells are only based in the liver and cannot be sampled in the blood. To solve this problem, they optimised the fine needle aspirates (FNA) method, allowing them to sample the liver in a relatively pain-free manner.

“Using this method, we can study liver immune cells and viral markers over time during therapy. We and others have shown that certain subsets of NK cells may be important in aiding the control of chronic viral infections.

“We will assess the function of these cells, along with their ‘energy’ demands, to see if they are more ‘exhausted’ compared to non-infected patients. We’re aiming to establish a ‘favourable’ NK cell subset and harness it to facilitate viral control, linking this with the level of virus in liver cells during treatment.”

This project will advance our understanding of immune cells and their interaction with the hepatitis B virus in liver cells during therapy. This work will also be vital for drug development in the search for a hepatitis B cure.