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Wonder organ – how the liver finds and destroys immune cells

A new study shows the liver destroys the cells responsible for rejected organ transplants.

Most people only think about their liver when recovering from a big night of drinking when it’s busily producing enzymes to break down the alcohol. But this “factory” of the body is vital for survival and supports almost every organ.

If you didn’t have a liver, you wouldn’t be able to store carbohydrates and you couldn’t produce the bile that helps you digest a greasy breakfast.

We’ve known for around 40 years that the liver also has the ability to regulate the immune system’s response to foreign cells.

Now some colleagues and I at the Centenary Institute have discovered how the liver fights the immune system. We’ve identified (in mice) that the liver engulfs and destroys T cells – the body’s defence troops.

Our work, published today in the journal Proceedings of the National Academy of Sciences (PNAS), could lead to new approaches to prevent transplant rejection. It could also change the way we fight hepatitis C and other chronic liver diseases.

The discovery

My colleague Dr David Bowen and I first realised the liver could eliminate the T cells responsible for rejecting transplanted tissue around ten years ago. The T cells are also responsible for killing cells infected with viruses.

A T-cell (blue/green) being drawn into a mouse liver cell (red).

We found T cells rapidly disappeared when they entered the liver but were puzzled about how and why this occurred.

It was only in 2004, when our collaborator Dr Alessandra Warren at Concord Hospital took electron microscopy pictures showing live immune cells (T cells) inside healthy liver cells, that we came up with the idea that T cells might be “eaten” by liver cells. This was a true eureka moment.

When I presented this concept to Volker Benseler, a talented German post-doc at the time (now the lead author of the PNAS paper), he was sceptical and thought the idea was crazy. But he accepted the challenge and went on to discover healthy mouse liver cells eating T cells.

Until then, this kind of “cell cannibalism” had only been seen in tumour cells.

Suffering from rejection

One potential benefit of the research is a reduction in organ transplant rejections.

About 200 liver transplants are performed in Australia each year and up to a quarter of the cases end in rejection.

In transplantation, the new organ is seen by the body as a foreign object: the spleen or lymph nodes tell naïve T cells to replicate and turn into killer T cells. They are then sent off kill the “foreign” cells.

What we found was the liver circumvented this process: liver cells signal to naïve T cells and destroy them before they have a chance to become killer T cells.

If we can harness the way the liver controls T cells, then there’s a chance that transplant patients won’t need their current daily cocktail of immunosuppressive drugs.

While these drugs reduce the risk of organ rejection, they essentially wreck the patients’ immune systems and leave them open to serious infection from otherwise minor illness such as colds.

The immunosuppressive drugs also predispose the patient to long-term heart disease and cancer.

Battling hepatitis

Another spin-off of this latest work could be finding a way to tone down the liver’s destruction of T cells and increase its defence against infections, such as hepatitis.

In Australia, 217,000 people are living with chronic hepatitis C and it’s estimated that 170 million people worldwide are infected with the disease, for which there is no vaccine.

With further bimolecular research, we could develop medications that exploit the signal pathways between the liver and the T cells. To defend against hepatitis C, we need to develop drugs that prevent T cells from being digested by the liver to encourage the generation of killer cells that will ultimately eliminate the virus.

For transplants, we need to develop drugs that do the opposite and promote T cell degradation in the liver.

It could be another ten years or more before any drug derived from this work enters clinical trials. But in the meantime, we’ve got some exciting work ahead of us.

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