Oct. 21, 2003 Imperial College London researchers report today in the Journal of Experimental Medicine that they have developed a novel strategy for effectively treating the symptoms of the most deadly type of flu.
Working with influenza A virus, they show in mice that their novel treatment eliminates symptoms by reducing the response of active T white blood cells by a third.
Flu A is the type of influenza responsible for pandemics such as the 1919 outbreak of 'Spanish flu', which globally killed more than 20 million people.
Unlike current attempts to prevent or treat flu, which rely on either yearly vaccinations that try to predict how the virus might mutate, or anti viral drugs that must be administered as soon as there is contact with the virus, this new treatment can be given after symptoms present.
Dr Tracy Hussell of Imperial's Centre for Molecular Microbiology and Infection and senior author of the paper, says:
"Three times in recent history the flu virus has evolved from a disease characterised by coughs and sneezes to a world killer. The recent SARS epidemic highlights how quickly a deadly virus can spread in modern society and we are long overdue for the next flu pandemic. The sobering reality is that influenza is one of the grand masters at evading human immune response.
"During flu infection the immune system has an 'all hands on deck' attitude to the viral assault. But it's this that causes most of the damage. The exaggerated immune response produces inflammatory molecules that lead to what's known as a 'cytokine storm'. Essentially too many cells clog up the airways and prevent efficient transfer of oxygen into the bloodstream.
"By selectively reducing this cellular load we've shown it's possible to eliminate clinical symptoms whilst effectively tackling and clearing the infection."
The body has two major classes of white blood cells, T and B lymphocytes. While B cells produce tailor-made antibodies that help the body remember and quickly respond to invaders, T cells patrol the body, seek out and destroy diseased cells. But the T cell response also produces inflammatory mediators that lead to the 'cytokine storm'.
Until now, treatments to eliminate the cytokine storm have focused on inhibiting all T cells. But this leaves the patient unable to clear the virus and susceptible to other infections. Dr Hussell's team have developed a way of down regulating a molecule known as OX40 that only targets T cells that have recently been alerted to the presence of the flu virus.
"OX40 sends out a 'survival signal' instructing activated T cells to remain in the lungs for longer to help fight the infection. However, because new cells are arriving all the time this prolonged presence is not needed," explains lead researcher Ian Humphreys of Imperial's Centre for Molecular Microbiology and Infection.
"Inhibiting this signal therefore allows T cells to vacate the lungs earlier whilst leaving behind a sufficient immune presence."
Using a fusion protein OX40:Ig supplied by the pharmaceutical company Xenova Research, the scientists were able to demonstrate that OX40:Ig blocks active T cells.
Results show six days after infection with flu, mice treated with OX40:Ig were indistinguishable from uninfected control mice. But infected mice that had not been treated lost 25 per cent of their body weight, appeared hunched, withdrawn and lost their appetite - all characteristic symptoms of flu.
When treatment with OX40:Ig was delayed for several days after infection, until the mice had lost 20 per cent of their body weight and OX40:Ig was administered, symptoms were reversed.
Re-infection also indicated that the ability of mice to respond to a second infection was not affected by the reduced T cell immunity during the initial infection.
Dr Hussell added: "There is tremendous scope for this treatment. Basically any disease that is characterised by an excessive T cell inflammatory response, whether in the lungs, in the case of Bronchitis, Asthma and Pneumonia, or in the joints, such as Rheumatoid arthritis, could be a candidate for this type of treatment. If the clinical symptoms of SARS are caused by an excessive immune responses it too could be effectively treated."
Facts about flu
There are three main types of influenza virus A, B and C. Of these, A and B are of most concern because of the way in which their genomes evolve.
The organisation and type of genetic material flu virus is made from helps it hide from the immune system. RNA viruses, such as flu have a higher mutation rate because they don't proof check their genetic material when they make new viral particles. As a result, there's a huge amount of genetic variability within a new generation of virus particles. Although many of the mutation will be detrimental there will be enough that are able exploit a weakness in the immune system.
Influenza A is particularly dangerous because it readily undergoes 'gene swapping' or reassortment. This means two strains of the virus can infect the same cell and swap genetic information. Add this to influenza's ability to infect certain animals and birds, and you have a situation where two very distinct strains can infect a cell and hybridise to create a new strain that is very different from anything the immune system has encountered before. It is this process of gene swapping that has been linked with the emergence of most pandemics.
About Imperial College London
Consistently rated in the top three UK university institutions, Imperial College London is a world leading science-based university whose reputation for excellence in teaching and research attracts students (10,000) and staff (5,000) of the highest international quality.
Innovative research at the College explores the interface between science, medicine, engineering and management and delivers practical solutions that enhance the quality of life and the environment - underpinned by a dynamic enterprise culture.
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