Research

Watch: Research into organ transplant rejection and myocarditis

BHF Professor Federica Marelli-Berg tells Sarah Brealey how her research into the immune system is fighting back against organ transplant rejection and myocarditis.

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Most of us never think about our immune system. It works silently to fight off infections and keep us healthy.

But it can also turn against us. One of the most dramatic examples of this occurs in organ transplantation, when the body rejects a life saving organ. To stop this, transplant recipients must take a cocktail of immunosuppressant drugs for the rest of their lives, plus other drugs to manage the side effects.

Professor Marelli-Berg is one of the country’s leading experts on the immune system. Her passion was spurred on by personal experience. “My daughters’ friend had a heart transplant,” she explains. “She was only nine years old. I was already interested in transplantation but it was abstract at that point. I read up on how long the transplant would last – hopefully forever, but the average is nine or 10 years. You do look at your own children – it could be them in the same position.”

That was nine years ago, when Marelli-Berg was a lecturer in immunology at Imperial College London. Today, she is BHF Professor of Cardiovascular Immunology at Queen Mary University of London – an appointment that puts her in a select group of the most talented heart researchers in the UK. Having been awarded the prestigious BHF Chair position, her aim is to focus on the wider effects of anti-rejection drugs. “These stop rejection but also shut down other aspects of the immune system,” she says. “Transplant recipients are more likely to die from infections or cancer than transplant rejection.”

The professor believes the solution is to develop drugs that are much more specific. “The aim of my research into transplantation is to block the immune system only as it relates to the heart,” she says.

Targeting T-cells

Professor Marelli-Berg believes T-cells may hold the answer to targeted immune blocking. T-cells, also called T lymphocytes, help the body recognise and remember specific threats, so the immune system can be activated to fight them. T-cells are involved in transplant rejection, so anti-rejection drugs are designed to wipe them out.

Professor Marelli-Berg is interested in how T-cells travel around the body and find their destination. She compares the body to the world. A lymphocyte needs to find the right country (an organ), then the city (an area of inflammation), and finally the house in that city – the location of the virus or bacteria the lymphocyte fights.

“T-cells have a kind of homing system,” says Professor Marelli-Berg. “What I’m studying is like the GPS that helps them find the right address. We thought if we can find the ‘area code’ for the transplanted heart, then we can stop the T-cells from going there and stop the transplant rejection.

Last year, we discovered the T-cell ‘area code’ for the heart

“And that is what we have done, fully funded by the BHF. Last year, we discovered the T-cell ‘area code’ for the heart. It’s a particular molecule found only in the liver and the heart, which allows the T-cells to go just to the heart.”

This discovery opens the way for drugs that can stop the rejection of a heart. In research trials, Professor Marelli-Berg and her team gave heart-transplanted mice a drug called crizotinib (already in use for lung cancer). The results were dramatic. “Normally you would expect all the transplanted hearts to be rejected,” she says. “But in the mice that we gave the drug to, 75 per cent survived indefinitely. The heart was not rejected.”

The same drug was given to mice after a skin transplant. The skin was rejected – clear evidence that the drug specifically targets the heart. “This is the first example to my knowledge of organ-specific immunosuppression,” says Professor Marelli-Berg. But she stresses that a treatment for human patients is still some way off. “We are talking about transferring this into humans, but we need to do more work. First, we need to confirm that the same T-cells are present in humans.”

BHF Professor Federica Marelli-Berg

Tackling myocarditis

Professor Marelli-Berg’s research into the immune system and the heart has a second important application. Myocarditis is an inflammation of the heart muscle. It can be caused by a range of viruses, including those that cause flu, chicken pox, glandular fever and sore throats or chest infections. Often, the immune system deals with the infection and the inflammation goes away in days or weeks. But sometimes the immune system overreacts and the inflammation lasts longer than the virus. In the worst cases, the person dies suddenly, or develops dilated cardiomyopathy, where the heart muscle becomes enlarged and can’t pump blood efficiently.

“In people who run a marathon and suddenly drop dead, we often find myocarditis,” says Professor Marelli-Berg. “It often doesn’t give symptoms until it is too late. Myocarditis is very difficult to diagnose, and there are no specific treatments. It is considered a rare disease, but may not be that rare, because it is under-diagnosed.

The dream would be to have a good treatment for myocarditis and a screening test

“Very often myocarditis clears up on its own, but because it is under-diagnosed it is hard to be clear about the impact. In the worst scenario it can lead to a young person needing a heart transplant.”

The professor and her team are looking for new ways to diagnose and treat the condition. At the moment, diagnosis requires multiple biopsies (tissue samples) of the heart. They are trying to perfect a simple blood test to diagnose myocarditis. The test would look for T-cells that follow Professor Marelli-Berg’s ‘area code’ molecule to the heart, where they can cause damage.

“One possible outcome of this research is that we reach the stage where measuring the cells in a blood sample will be possible before joining a gym or running a marathon, to see if they have any inflammation,” she says. “The dream would be to have a good treatment for myocarditis and a screening test. But this is going to be long term.”

One aspect of the work is to study where lymphocytes (specialist white blood cells that include T-cells) get the energy they need. There may be drugs that could affect their energy supply, such as metformin, which is already used to treat diabetes. The hope is that drugs like this could target the immune system without the negative side effects of traditional immunosuppressant drugs.

Myocarditis

Microscopic view of myocarditis (viral inflammation of the heart)

Making a difference

A few months ago, the BHF arranged for Andy Maiklem, 41, a heart transplant recipient who developed myocarditis at the age of 28, to visit the professor’s lab and see her work.

“It was such a humbling experience for me to meet a patient who has been through all that,” she says. “My fascination as a scientist has been looking at the cellular processes, which are amazing, but you never lose sight of the disease and the people your research could help.

“My biggest ambition is to see my research being used for patients. That is my dream, before I retire.” 

As one of the BHF’s most senior researchers, and the leader of a team of 20 scientists at Queen Mary University of London, Professor Marelli-Berg is now thinking beyond her own research. “There are very talented people that I am mentoring,” she says. “It’s like being a parent, in that you want people to have the opportunities you didn’t have. The university and the BHF are helping me to give them those opportunities. What I want to do is help raise the next generation of scientists. That is what I want to be my legacy.”

Seahorse machine, which can measure cell metabolismSupport from the BHF

As part of her appointment as a Chair of Cardiovascular Immunology, the BHF funded Professor Marelli-Berg £120,000 for a machine named the Seahorse (pictured right).

The machine lets researchers measure cell metabolism, for example by measuring oxygen that cells consume. Different drugs can be added to the cells in the machine to see the effect on cell metabolism.

“The Seahorse analyser is really state-of-the-art,” says Professor Marelli-Berg. “It is proving a powerful tool. It means we can look at the metabolism of immune cells in real time. It is crucial for the studies we are doing on different drugs as immunomodulators. Other BHF-funded colleagues are able to use it too.”

The machine is so important, it was the first thing on the professor’s mind after a break-in at the university. “When I found out, I was out of my mind with worry about the Seahorse,” she says. “I asked the police to go and check if it was OK. That machine was the most important thing to me.”

The Seahorse is part of the £1.2m funding we awarded with her appointment as a BHF Professor. But she says BHF support has gone far beyond this. “The BHF made me what I am now,” she says. “My first grant was from the BHF. It is not just the money, it is also the mentorship. I can make an appointment with Jeremy Pearson [BHF Associate Medical Director for Research] and he will always advise me.

“The BHF has helped me at times when I thought I wasn’t good enough. The first time I applied for the Programme Grant, I didn’t get it, but they explained what I needed to do better. That really helped me and it made me want to work harder.”

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