Science: A drug for every bug

That getting sick in the short term may help your health in the long run is well established. From that theory comes a vaccine which may act against all stimuli of asthma. By David Spark

If you have had measles, or were once infected with tuberculosis without showing symptoms, or are the youngest in your family and live an unstressed life, you are less likely to suffer from asthma, hay fever, cancer and possibly even ME (chronic fatigue syndrome). Those are the statistical facts. Now, a new understanding of why this should be has opened a new avenue for tackling diseases by vaccination. A vaccine is in its final trials to speed the cure of TB, an increasingly drug-resistant bacterial disease. It is also being tried against lung and other cancers. Trials against asthma and hay fever are in the offing.

The beauty of using this approach to asthma is that it should be effective against all allergens causing the disease. Most other vaccines under study will only work against one allergen - say, the house dust mite - and sufferers will need further vaccination against, say, cat hairs. Similarly, the new vaccine should stimulate the immune system against any cancer cell flagged, as most are, by heat-shock proteins on its outside.

The story began in Uganda, where BCG vaccination of children against TB works wonderfully. Yet in some other countries, it does not. So is the difference in the people, or the batches of vaccine? Dr John Stanford of University College London decided it was neither: Ugandans, he reckoned, must be meeting some other organism before BCG. He screened for a vast number of organisms similar to BCG in the Ugandan environment and finally decided on a particular one of them, Mycobacterium vaccae.

What he and an immunologist colleague Professor Graham Rook came to realise is that this organism stimulates action in the bloodstream by the Th1 lymphocyte, a cell which alerts the immune system and begins the fight against infection. M vaccae stimulates Th1, or at any rate, reduces the number of a rival lymphocyte, known as Th2. When challenged by TB infection, Th1s prime macrophage cells - the hunter-killers of the immune system - to attack the tuberculosis bacterium. They also release toxins to kill macrophages overcome by the infection. TB does not develop.

However, if there are also Th2 lymphocytes in the bloodstream, the reaction is more drastic. The historical role of Th2s is to drive worms out of the gut. Faced with TB bacilli, they cause destruction of the surrounding lung tissue. This hinders, not helps - infection can take hold in the holes that are created.

What BCG does is amplify the immune reaction, whether it be a Th1 reaction or a mixture of Th1 and Th2. This explains the variability in its effect.

Stanford and Rook formed Stanford Rook Ltd to produce SRL 172, a vaccine based on M vaccae. It is now undergoing final trials involving 380 people as a means of speeding the cure of TB. Drugs can quickly reduce the scale of a TB infection, but they have to be continued for six months for a complete cure. SRL 172 should stimulate Th1 lymphocytes to finish the job quicker, and should also help some of the many HIV sufferers around the world who develop TB through opportunistic infection.

The idea of stimulating lymphocytes to attack cancer cells is not new. BCG has been tried, and is the standard treatment for cancer of the bladder. But SRL 172, stimulating Th1 lymphocytes, should have an advantage. Th1s organise cell-killing toxins. Cancer patients tend towards Th2.

SRL 172 also contains heat-shock proteins similar to those expressed by human cells under stress. It should help Th1s to recognise the high level of these proteins on cancer cells. In a pilot study of SRL 172 against skin cancer, carried out by Professor Angus Dalgleish, nine of 36 patients showed improvement.

Oddly, although SRL 172 has nothing in common with allergens, Stanford Rook Ltd found that it diminishes allergic reactions in mice. It seemed an odd, random result. Then Science magazine published a paper reporting from Japan, where children are repeatedly vaccinated with BCG against tuberculosis until they show a Th1 response.

The paper showed that children with this response are also less likely to have allergies. If this result could be achieved by BCG, there was a clear opportunity for a vaccine specially designed to stimulate Th1s. Hence the upcoming trials, against hay fever in Oxford and asthma in Southampton. "It's quite exciting, really," says a leading asthma expert, Professor Stephen Holgate of Southampton University.

The main cause of asthma is the frenzied response of Th2 lymphocytes to allergens, especially dustmite droppings, arriving in the lungs. Among other things, the Th2s summon powerful cells called eosinophils. These slough off the allergen, and with it the hairlike cells on the lung surfaces, leaving the lung unprotected against further irritation. The result is asthma.

Professor Holgate believes that asthma has become more common because there are fewer Th1 stimuli in today's less germ-laden homes. Professor Rook has also noted that vaccination against whooping cough promotes Th2s. A study in Guinea Bissau showed children who had had measles were less allergic. "Getting better from measles is a victory for Th1s," says Professor Rook.

A study in Germany showed asthma to be less common in the east, where small children spent more time in groups and creches, able to pass on minor infections to one another. This is similar to the finding that a family's youngest child - open to infections from older ones - is best protected against asthma. Getting ill in the short term can be good for you in the long run.

Professor Clive Page of King's College, London, points out that small children nowadays spend longer in their homes, where there are fewer draughts and open windows to blow away allergens. Professor Holgate says that sensitisation to allergens can start in the womb. Patients often use steroid sprays against asthma. These wipe out the Th2 response. Unfortunately, according to Professor Rook, they also make the immune system tend to produce Th2. Clive Page holds out hope for another drug, theophylline, which might be given in tablets instead of through inhalers. It is similar to the caffeine in coffee, which has been known as an asthma treatment since the 18th century. He is especially keen that young asthma sufferers get treatment before the drastic eosinophil response takes hold.

Professor Rook has added a further hypothesis in an article in The Lancet. It is that ME (chronic fatigue syndrome) and Gulf War syndrome may both result from Th2 activity. Vaccination against tetanus, required for the Gulf, stimulates Th2 cells as these are needed to fight tetanus toxins. Th2s are also promoted by cortisol, a steroid produced in people under stress. Blood tests could show whether ME sufferers and Gulf veterans tend towards Th2.

It's a long shot, but the sort of finding which links together many different ideas in a subtle, but enormously helpful collection. What it really needs, though, is the findings from the trials - and those will take some years to be concluded n

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