Hopes for human drug raised as damaging inflammation curbed in mice.
23 October 2003
Nature News Service
Researchers in Britain may have invented a new way to treat flu. Promising results in mice could lead to human trials.
The therapy dampens the body's response to infection. It might also work for other diseases in which our defences overreact, such as asthma or multiple sclerosis, says one of its developers, Tracy Hussell of Imperial College, London. "There are many situations where the immune system goes mad," she says.
Unlike vaccines or antivirals, the new drug attacks the symptoms of flu rather than the virus itself. So it should be unaffected by strains that mutate to dodge more direct attacks.
"It clearly has potential," says immunologist David Gray of the University of Edinburgh. Similar anti-inflammatory drugs are already used to treat rheumatoid arthritis, he says, but other options would be welcome: "One could have a whole range of these drugs to pick off the shelf for a particular disease."
The researchers studied mice infected with influenza A. This strain caused the Spanish flu pandemic of 1918-19, which killed more than 20 million people worldwide.
There is no guarantee that the drug will work in humans. "Flu isn't a natural infection of mice," warns influenza expert Alan Hay of the National Institute for Medical Research in London. "But it's certainly something worth following up," he says.
A body with flu can be its own worst enemy. Immune sentries called T cells rush to the lungs, releasing chemicals that cause inflammation. This can be life-threatening: it blocks blood vessels cutting off the body's oxygen supply.
It is not clear why we mount such a counterproductive defence. It may be that the deep recesses of our lungs are unaccustomed to foreign bodies, and so respond with unusual vigour.
Hussell's team stops these overzealous T cells loitering in the lungs. Their treatment blocks a molecule on the cells' surface called OX40. Normally, OX40 is switched on about two days after a T cell meets the flu virus, prolonging the cell's life. The protein that blocks OX40 was originally developed to treat inflammatory bowel disease.
The drugged body can still defend itself. T cells stream into the lungs, but not in numbers that cause severe inflammation. The cells are efficient virus-killers in the two days before they switch on OX40, and those that have not encountered flu carry on as normal.
Infected mice normally lose a quarter of their body weight, and become feverish. A drug dose three days after exposure kept them healthy1. "They didn't look infected at all," says Hussell.
Wrong diagnosis should not be a problem, Hussell adds. Common cold viruses produce the same immune response, and the treatment should work just as well.
The researchers are seeking funding for a clinical trial in healthy humans and, if that goes well, in asthmatics. Barring any setback, a drug is five to ten years away.
1. Humphreys, I. R. et al. A Critical Role for OX40 in T Cell-mediated
immunopathology during lung viral infection. Journal of Experimental Medicine,
198, 1237 - 1242, doi:10.1084/jem.20030351 (2003). [Article]
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