Touching Lives - March 2006
Boosting fragile immune systems
Humans have two main forms of defence against infection. The first you are born with and is called the innate immune system. The second develops after birth and is known as the acquired immune system. This provides a memory of all the infections we get throughout life.
The acquired immune system takes time to develop, so babies and children rely heavily on the innate immune system for their defence against infection. This makes them more vulnerable to infections than older children and adults.
In these early years, a protein called mannose binding lectin (MBL) is particularly important for attacking the viruses, bacteria and fungi that can cause infections. This protein recognises sugars on the surface of these infectious organisms and binds to them. Once bound, it can kill the organism and then help clear it away so that it can no longer cause harm.
Seventeen years ago, Action Medical Researcher, Professor Mac Turner, who was based at Great Ormond Street Hospital (GOSH), discovered that some people have low levels of MBL in their blood. In fact, this deficiency of MBL is quite common, with about a third of the population affected. Subsequent work, (some of it funded by Action Medical Research) has shown that low levels of MBL put children at greater risk of getting infection.
Most of the time these infections are what we would consider minor, such as coughs and colds. But the findings do go a long way to explain why some children seem to always get coughs and colds while others get through childhood with very few infections.
Levels of MBL are determined by our genes, so children within a single family can have different levels of MBL and therefore different frequencies of infection. For example, if a mother has low levels and the father has normal levels then only some of their children will have low MBL levels.
While most infections in children with low MBL levels are minor, there are a few infections that are more serious. These are the ones that cause meningitis (infection of the surface of the brain) and septicaemia (severe infection of the blood). These are uncommon, but when they occur they are serious and can be fatal. Advances in intensive care and earlier recognition of symptoms by parents and doctors have improved outcomes for children. But serious infections are still responsible for many admissions to intensive care units and many deaths.
More recent Action Medical Research funding enabled researchers to investigate exactly how MBL helps to protect children from these infections, and they found that MBL seems to be particularly important in preventing children from getting septicaemia.
In a study of nearly 200 children admitted to intensive care, nearly all of those with septicaemia had low levels of MBL. Children who had normal levels of MBL were very unlikely to get septicaemia. This evidence seemed to suggest that if MBL could be administered as a treatment, it could help to protect children with low levels of the protein from both coughs and colds, as well as more serious infections like septicaemia.
Developing a treatment
Armed with this theory, researchers have been looking at how MBL might be developed as a treatment for patients. Professor Nigel Klein, who has been involved in the research regarding MBL and serious childhood infection for a number of years, says “In recent months efforts have been made to manufacture MBL as a recombinant protein [inserting the gene which codes for MBL into bacteria to produce the protein on a large scale - Ed]. Initially we could only manufacture it by purifying it from blood, but there are certain dangers associated with using blood products.
“The good news is that we are now able to culture the protein in the laboratory, meaning that there should be far fewer complications when it is given to patients.” Importantly, the treatment already has commercial backing, and is due to enter multi-national clinical trials in the near future. Dr Klein is on the advisory panel for the company that plans to manufacture the treatment. He explains, “At the moment we are working together to establish which patient group will be best to begin the trials in. People undergoing chemotherapy are particularly suitable as their immune systems are low.”
Since Professor Turner’s initial findings on MBL some years ago, researchers have realised that the benefits of the protein extend far beyond protecting children from the common cold. Dr Klein explains, “MBL is far more crucial than we’d realised before. While it can help protect children against both minor and serious infections, it could also be hugely beneficial to adults whose immune systems are vulnerable.”
From treating to preventing
“The major strength of this treatment is the broad spectrum of protection that it could provide. If the treatment trials are successful, we could see it being used in patients in intensive care, in cancer patients undergoing chemotherapy — even people who have had complex surgery. Such people all have low immunity, and infection can often complicate and prolong their recovery. By boosting their MBL levels, we could see a vast reduction in infection complications, leading to a much reduced need for antibiotic treatments, and therefore fewer cases of antibiotic resistance.
“Essentially, if MBL works as expected, we should see a shift from treating infection to preventing it, which is far more effective medicine.” Professor Klein and his team are currently preparing papers on their findings on MBL and its role in controlling infection for publication in medical journals. He says, “Action Medical Research’s funding has been extremely important in helping us get to this point.The potential for a treatment that can increase people’s MBL levels really is hugely exciting, because of the numbers of people that stand to benefit. I am not aware of any other work going on in this field that could have the same impact.”