Protein that helps cure disease

 

Trinity College researchers have discovered a new target for slowing down inflammation, possibly leading to new treatments for a wide range of diseases, writes Dick Ahlstrom.

A team of researchers who developed a powerful treatment to help patients with meningitis have made a fresh discovery that could help produce therapies for a much wider range of illnesses.

The work centres on elements of the body's immune system, the cells and substances that protect us against infection. While the immune response to viruses and bacteria can keep us alive, its over-response is a common cause of death for patients in intensive care.

Details of the research work were published recently in the British Journal of Haematology. The team leader is Prof Owen Smith, a clinical investigator and paediatric haematologist at Trinity College and St James's Hospital and Our Lady's Hospital for Sick Children, Crumlin. It includes five student researchers including lead author Leona Galligan, who is working towards a PhD.

Prof Smith discovered how a protein known as Protein C could help reduce deaths caused by blood poisoning or sepsis brought on by acute infections such as meningococcal meningitis. The administration of Protein C to sepsis patients helped to reduce mortality from about 50 per cent to 10 per cent. He published details of this work in the leading journals, Lancet and Blood.

The results of world trials last year showed that giving patients a different form, activated Protein C, could reduce deaths of patients in intensive care, further demonstrating the value of the treatment.

Protein C works because it has a powerful effect on the immune system, dampening down substances known as cytokines that act as messengers to activate various parts of the overall immune response. Biochemists were interested to know how Protein C did this and began searching for cell "receptors", places where the protein could attach to trigger a response.

A Japanese scientist, Dr Kenji Fukudome, identified and isolated a Protein C receptor found in endothelial cells, the cells that line blood vessels. Now the Trinity team has identified a second receptor, this time on white blood cells called monocytes.

"What we have discovered is the monocyte has a Protein C receptor that nobody has found before," says Smith. They had suspicions that the cell would have a Protein C receptor because of the key role monocytes play in septic shock. They are one of the first cells to encounter the bacteria that cause it and can also release many of the key inflammatory cytokines, such as interlukin.

Prof Smith reasoned that if the monocytes could promote cytokines, they would also probably have a method to retard cytokine action. Finding a monocyte receptor site for the strongly anti-inflammatory Protein C showed that this was so.

Galligan and the team found the receptor by using an antibody developed by Dr Fukudome. They then identified the gene involved with the receptor and sequenced the gene's DNA. They found that it was identical to the endothelial cell gene sequence discovered by Dr Fukudome.

The finding is important because "it opens up the whole area of novel therapeutic targets to try and control inflammation," Prof Smith states.

As well as blocking inflammation, Protein C can also prevent inappropriate blood clotting and could have a use against rheumatoid arthritis and the autoimmune disease lupus. It could also be used to help protect the liver in bone marrow transplants.

Radiation and powerful drugs are used to kill off diseased bone marrow, and the by-products from this are filtered and concentrated in the liver, Prof Smith explains. Liver tissue called Kuffer cells release cytokines when under stress, and this damages vascular tissues and harms liver function. Protein C might provide a way to head off this damage.

The research project has been particularly fruitful for Galligan. Her efforts won best science project at the all Ireland Haematology Society meeting.