Science Spin September 2008 : Sponsored Content - Science Foundation Ireland

Understanding the 'arms race'

By Sean Duke

For millions of years there has been an 'arms race' in our body. Viruses, bacteria and parasites are constantly evolving new ways to gain admittance to the body, while sophisticated cells of our immune system are continually developing ways to find and destroy the intruders. The name of the game for the intruders is to sneak into the body under the radar, avoid detection, and to go about causing infection and disease. As they evolve they get better at this over time, but the defenders too are evolving all the time.

Researchers at the Immunology Research Centre, or IRC, based mainly at TCD, are aiming to give the body's defenders an edge, by understanding more about how unwanted intruders can be identified and destroyed before they cause a serious illness, or infection. The key area is the early responding defender cells of the innate immune system, that rush to the site of infection, tackle the intruders, and call for 'back up' from other cells.

The lead PI on the project is Professor Kingston Mills at TCD. Prof Mills said that the cluster brings together the best immunology talent in Ireland. The IRC is a Strategic Research Centre has support of €2 million from SFI over five years. Aside from Professor Mills there are nine other Principal Investigators (PIs) involved in the IRC, including some true world-class names, such as Professor Luke O'Neill, and Professor Seamus Martin, both TCD.

There is a strong industry connection too, with links established with Schering Plough, an important multi-national based in Ireland. There is also a TCD spin-out company, called Opsona Therapeutics, which was set up by Professor Mills, Professor O'Neill, and Mark Heffernan. The company states that it is involved with regulation of the immune system.

The link with Schering Plough is regarded as a major plus for the IRC as Schering has a high profile in the immunology field, with a prestigious research institute, the Dynax Institute located in Palo Alto California. Opsona meanwhile is primarily focused on the development of anti-inflammatories, and is based at St James's Hospital in Dublin.

Goals

The IRC aims to discover new activators or inhibitors of innate immunity, said Professor Mills. Innate immunity is critical, he explained, since it is the first line of defence against infection. This system, unlike the adaptive immune system, doesn't need to be mobilised and responds very rapidly, with cells arriving at the infection site an hour or two after the infection is picked up. These important cells are called macrophages or dendritic cells.

The cells of the innate immune system are crucial and act like an early emergency response team. In addition, they also act to direct the response of the adaptive immune system. So, everything that happens in the immune system has to go through the innate response. This led the IRC researchers to consider how to active the innate response.

An agivant is something that activates the innate immune system, and generally it is a part of a virus or a bacteria, or even a piece of a host cell. In the old days, said Prof Mills, whole viruses or bacteria were used to activate the immune system in experiments, but by using agivants that is no longer necessary. It's a far more targeted approach than before.

Patterns

DAMPS (danger associated molecular patterns) and PAMPS (pathogen associated molecular patterns) were terms coined by the late Charles Janeway of Yale University, explained Professor Mills. The idea here is that the body doesn't necessarily respond to something that's foreign, but rather it responds to something that it considers dangerous. Danger to the body can come in the form of viruses or bacteria, but it can also come in the form of dead or dying cells -- the latter indicating that there is something wrong. One of the lead PIs in the IRC, Professor Seamus Martin, is an expert in the area of cell death, or apoptosis, and one of his remits is to discover new DAMPS. These are essentially the products of dead or dying cells that release molecules that activate the immune system.

It is important to understand that the immune system responds to its own dying cells, not just viruses, bacteria and parasites. This is important, for example, when trying to find new therapies for cancer. In cancer, the gaol would be to up-regulate the immune response, so there is a stronger response. The response in this case would be to the body's own cells that have become cancer cells. The agivant that is sought in this case would be the component of the cancer cells that indicate that these cells have become cancerous.

Inhibition

The other part of the IRC's work is to discovery inhibitory molecules. That is molecules that inhibit, or tone down, the response of the body's immune system. This is very important in auto-immune diseases such as arthritis, multiple sclerosis, and type 1 diabetes. "These are diseases where the immune system is out of control," said Prof Mills.

The immune system is responding to its own cells, and this is not desirable. So, another major objective of the IRC is to discovery 'suppressor molecules' that can turn off the immune system. It turns out, not surprisingly, that viruses, bacteria and parasites are very good sources for these suppressor molecules. Over millions of years, these organisms have developed ways of turning off the immune system of the body.

"They have done all the hard work for us," said Prof Mills. "You find the mechanism that the virus or bacteria is using to turn off the immune system, because it wants to evade the immune system or subvert it. We discovered molecules that were taken out of the context of the virus or bacteria and used them as therapeutic drugs, or targets for developing new drugs against auto-immunity."

Cancer

A new immunological approach is being developed for cancer, and for other situations, such as chronic Hepatitis C infection, where the patient is very immuno-compromised. The problem in these cases is that it is very hard to activate an immune response in what is a very immuno-suppressed environment. The approach here, therefore, is to take cells out of the stressful environment, activate them, and put them back into the body. In the case of cancer, this would involve removing some of the tumour surgically. There is evidence that this approach has worked in animals, said Prof Mills, and it is likely to become more important with companies moving into clinical trials in the USA.

Future

The work of the IRC will ultimately lead to new products, new immunotherapies, but this is unlikely to happen during the five-year lifetime of the project. At the end of the project, however, it is likely that the researchers will have identified interesting molecules with the potential to be developed as drugs. These could be agivants for vaccines, or immune boosters for cancer, or immune suppressors for auto-immune disease. The researchers are particularly focused on efforts to find new treatments for TB, malaria and inflammatory bowel disease, and new vaccines, and there is a lot of talent involved in these efforts.

"We have some very high profile individual PIs," said Prof Mills. "The evidence is based on citation impact analysis for papers. Based on the size of the country we are ranked two in the world. We are planning a new building which has started, on Pearse Street, opposite Westland Row. What we are building there is a Bio Sciences institute which will include all the Immunology initiative in the College (TCD), and hopefully this will be a major boost to our immunology programme and the idea is the SRC would be housed mainly in that building."