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Transplant surgery is at the glamorous, high-profile end of medicine; treating asthma certainly is not. Yet the success of both depends on doctors being able to manipulate the body’s immune system, to prevent organ rejection in one case and the overzealous immune responses which appear to cause asthma attacks in the other. Given this link, might drugs that successfully prevent organ rejection also work as therapies for asthma? And could researchers use their knowledge of the immunology of organ rejection to solve the biological puzzle of asthma?

At the National Heart and Lung Institute in London we are trying to find out. Over the past six years we have been searching for clues as to what goes wrong in the immune systems of people with asthma, asking whether the faults can be corrected with substances such as cyclosporin A, a drug which has been used for the past decade to suppress immunity in transplant patients. Our optimism is now greater than ever, and for two good reasons.

First, several lines of research now suggest that immune cells known as helper T cells are the prime movers in asthma: people with the disorder somehow become hypersensitive to things such as dust and pollen, with the result that they produce overactive helper T cells. Secondly, T cells are the very type of immune cell targeted by cyclosporin A in transplant patients. Last year the initial results of clinical tests of cyclosporin A in asthma sufferers produced the first evidence that the drug might eventually double up as a treatment for asthma (New ÐÓ°ÉÔ­´´, Science, 15 February 1992).

But the human immune system depends on a bewilderingly complex network of interactions between different types of cells – helper T cells, B cells, killer T cells, neutrophils and so on – and families of messenger molecules such as cytokines. Each type of immune cell specialises in a particular task: B cells produce antibodies, killer T cells destroy tumour cells or virus-infected cells, helper T cells support and control other immune cells, and so on. Yet all components of the immune system needs to communicate with one other. How realistic is it, then, to expect to be able to use a drug to knock out one problematic component, a group of overactive T cells, say, without severely weakening the entire system?

Hopes of tackling such issues must rest with our ability to unravel the complexities of the immune system. With asthma the potential rewards of doing so are especially great. It is one of the commonest chronic diseases in the West. It currently kills about 2000 people each year in Britain, and its incidence is rising. Most asthma sufferers inhale corticosteroids to control their symptoms. These substances, which are produced naturally by the adrenal gland, and normallly released in response to stress, reduce the inflammation that is one of the main symptoms of asthma and other immune disorders such as rheumatoid arthritis. Since corticosteroids were first isolated in the 1950s, they have given relief to millions of asthma sufferers.

SIDE EFFECTS

Inhaled as a spray directly into the lungs, such steroids produce few side effects. But between 3 and 5 per cent of people who suffer from asthma – 200 000 to 400 000 people in Britain – require such large doses of steroids that they can only be administered orally. For them there is a real danger of side effects, including osteoporosis and diabetes. In addition, about 10 per cent of people with the worst cases of asthma are resistant to treatment with steroids. It is primarily for these groups that alternatives to steroids are sought.

Resistance to steroids is common in people suffering from so-called ‘intrinsic’ asthma, for which there appears to be no external trigger. The more common ‘extrinsic’ asthma, which is usually less severe, is triggered by exposure to irritants such as pollen or dust. Whereas extrinsic asthma tends to afflict children and young adults, and is generally easy to treat, intrinsic asthma usually starts in mid-life and is sometimes so severe as to be life-threatening. The causes of extrinsic asthma attacks are often clear, and although the same is not true for intrinsic asthma attacks, the immune system appears to be involved in both.

Despite all this, most explanations of asthma fail to distinguish between intrinsic and extrinsic asthma. The standard theory draws on two main ingredients: a class of immune cells known as eosinophils, which can cause inflammation, and a class of antibodies known as immunoglobulin E (IgE), which in large quantities can trigger spasm of the bronchial muscles, and so cause wheeziness. It is not hard to see how these two ingredients combine to produce extrinsic asthma. When healthy people inhale a foreign substance, or antigen, the immune system responds by instructing some of its B cells to pump out antibodies, which act either to neutralise the invader or to summon killer T cells to the site of invasion. The problem for people with extrinsic asthma is that they are genetically predisposed to produce large amounts of IgE in response to certain inhaled allergens – the antigens to which they are particularly sensitive. IgE has a penchant for binding to mast cells in the lining of the lung. When these cells come into contact with both IgE and an allergen, they release a shower of substances whose mission is to protect the body against invaders. Some of these substances, notably histamine, and three groups of lipid molecules called leukotrienes, prostaglandins and platelet activating factor (PAF), also encourage muscular contraction and thus lead to wheeziness.

By contrast, what causes wheeziness in people with intrinsic asthma is still a mystery. However, as in extrinsic asthma, inflammation is a marked feature, as is the involvement of eosinophils. Like mast cells, eosinophils unleash defensive substances when they encounter antigens. Inflammation is caused by some of these substances – notably, PAF, leukotriene C4 and major basic protein (MBP) – damaging the cells that line the airways. These substances also expose nerve endings, which can worsen any irritability.

So what causes this inflammation, and what controls it? The answer seems to lie with the T cells. In the mid-1980s an instrument called a flexible fibre optic bronchoscope began to be used in asthma research, to examine the airways of patients under local anaesthetic, and to obtain material for biopsy. At round the same time, a technique called bronchoalveolar lavage also began to provide samples of lung fluid and cells.

At the National Heart and Lung Institute, we used these techniques to compare sufferers from mild extrinsic asthma with normal volunteers. As expected, we found substantial numbers of eosinophils in bronchoalveolar lavage from those people with asthma but virtually none in the controls. Similar numbers of T cells were obtained from the two groups, but we were surprised when Peter Jeffery found that irregular shaped T cells were four times as prevalent in biopsy material from people with asthma as from the normal volunteers. Further research showed the surfaces of these cells to have lots of receptors for interleukin-2, a protein that stimulates T cells to grow. As an immunologist would say, the cells have been ‘activated’. The most likely explanation for T cells being activated in this way is that they have encountered antigens.

Traditional explanations of asthma place little emphasis on T cells, largely because it was felt that all asthma could be explained in terms of mast cells and eosino-phils. It is well known, however, that T cells respond directly to allergens and other antigens. Our results prompted us to look again at the findings of Tim Mosmann and colleagues at DNAX, California. In 1986, they discovered that helper T cells, which support and control other immune cells, can be divided into two types – THl and TH₂ – on the basis of the cytokines they produce. TH1 cells produce cytokines that are characteristic of the immune response to tuberculosis and some bacterial infections, including tetanus. The cytokines produced by TH₂ cells are characteristic of allergic responses.

At the National Heart and Lung Institute, Qutayba Hamid, Douglas Robinson and Stephen Durham began to look at the types of cytokines produced by people with extrinsic asthma. Working with Christopher Corrigan, they found unusually high levels of a cytokine called interleukin-5, which is produced by TH₂ cells. Interleukin-5 not only activates eosinophils, encouraging them to release their offensive substances, but ‘instructs’ precursor bone marrow cells to differentiate into mature eosinophils. People with extrinsic asthma also seem to have high levels of interleukin-4, another powerful messenger protein produced by TH₂ cells. This is especially interesting because interleukin-4 encourages B cells to produce IgE.

So what can we conclude from all this? The picture is still incomplete but it seems that asthma attacks – the acute symptoms of extrinsic asthma – may largely be the work of mast cells and the substances they secrete, while the chronic inflammation results from the action of TH₂ cells on eosinophils (see diagram). A further question is what, if any, bearing these fresh clues to extrinsic asthma have on intrinsic asthma, where inhaled allergens, mast cells and IgE are not involved.

Andrew Bentley at the National Heart and Lung Institute and Gunter Menz at the Hochgebirgsklinik in Switzerland have recently used fibre optic bronchoscopes to study people with intrinsic asthma. As with extrinsic asthma, the lung fluids of these patients contained unusually high levels of eosinophils and activated T cells. If, as initial results from other studies suggest, these T cells produce interleukin-5 (which stimulates eosinophils) but not interleukin-4 (which stimulates B cells to produce IgE), then the major difference between extrinsic and intrinsic asthma is clear. In other words, the TH1/TH₂ story does not seem to hold up in intrinsic asthma.

What all these studies show is that both intrinsic and extrinsic asthma depend critically on helper T cells. Like all T cells, TH1 and TH₂ cells spring into action only when triggered by antigens. In the case of extrinsic asthma these antigens are likely to be inhaled allergens, but what type of antigen could be activating helper T cells in the lungs of patients with intrinsic asthma? One possibility is that the antigen originates in an infectious agent such as a virus. Another is that it is one of the body’s own substances which the immune system no longer recognises as ‘self’.

As the evidence implicating helper T cells in asthma mounts, doctors looking for alternatives to oral corticosteroids for treating severe asthma are turning to drugs that target T cells. The prime example is cyclosporin A, a peptide extracted from the fungus Tolypocladium inflatum, which has been used for almost a decade to suppress organ rejection. It works by disabling the gene for interleukin-2, so that T cells cannot respond to antigens. In 1987, I approached Sandoz, the company that manufactures the drug, for support for a clinical trial of cyclosporin A in asthma patients. At that stage the drug had already started to be used with some success to treat a range of so-called ‘autoimmune’ diseases, including rheumatoid arthritis, psoriasis, the inflammatory bowel condition known as Crohn’s disease and chronic uveitis, an inflammation in the eyes.

Initially, Sandoz were reluctant to back the study, arguing that the link between helper T cells and asthma was still unproven. But they did agree to provide free drugs, and in 1989 Andrew Alexander and Neil Barnes designed a three-month trial to test efficiency and safety, which went ahead with 32 volunteers. The results were promising, and a nine-month trial designed to test whether patients can be weaned off oral steroids is now under way with backing from Sandoz.

Although cyclosporin A curtails the action of a prime player in the immune system, at low doses it does not appear to increase susceptibility to infectious diseases. When taken in high doses, it does, however, have a well-documented history of side effects, including renal toxicity and, to a lesser extent, liver damage and hypertension. Volunteers were screened for impaired kidney function before entering the trial. Each then received a daily dose of 5 milligrams of drug per kilogram of body weight. The usual daily dose for transplant patients immediately after surgery is 15 milligrams per kilogram, gradually falling to 5 milligrams. Above this lower level kidney toxicity increases dramatically.

In the first trial, cyclosporin A supplemented the normal intake of corticosteroids. Patients monitored their own progress twice a day with take-home peak flow meters, which measure lung power and to what extent the airways are blocked. Nobody’s condition deteriorated, and there was an average improvement in lung function of nearly 18 per cent. The beneficial effects appeared to continue for several weeks after the three-month trial had ended, and almost all the original volunteers, most of them chronic asthma sufferers for up to 25 years, are participating in the second, longer trial.

Despite these promising results it is unlikely that cyclosporin A will ever be more than a stop-gap measure, as the danger of side effects increases considerably with long-term use. Less toxic alternatives are likely to be available within five years. Researchers have their sights on a compound called FK-506, an antibiotic-like ‘macrolide’ isolated from mycobacteria, which is 10 to 100 times more potent at inhibiting T cells than cyclosporin A. FK-506 has performed well in initial trials on transplant patients. In laboratory experiments, another macrolide, rapamycin, has been found to be more potent than cyclosporin A as an inhibitor of T cells.

Novel treatments for asthma may emerge as spin-offs from other lines of research. Monoclonal antibodies, for instance, have been tested against diseases as diverse as rheumatoid arthritis and multiple sclerosis. Monoclonals against the interleukin-2 receptor have already been used successfully in clinical trials to inhibit organ graft rejection, so monoclonal antibodies against activated T cells or interleukin-2 receptors might be effective against chronic asthma.

A more subtle approach would be to prevent T cells and eosinophils from reaching the site where they will cause damage – the lining of the lungs. T cells migrate to sites of infection in the body with the help of ‘sticky’ proteins known as cell adhesion molecules (‘A sticky end for disease’, New ÐÓ°ÉÔ­´´, 5 December 1992). Many researchers are attempting to develop antibodies that block these sticky substances in the hope that they might prevent T cells migrating to attack freshly transplanted organs. Some biotechnology companies want to treat chronic asthma in this way. The German drugs company Boehringer-Ingelheim has produced anti-intercellular adhesion molecule-1 and successfully used it to prevent asthma in monkeys. Ultimately, human asthma sufferers could possibly benefit from such antibodies if they can be produced cheaply enough.

A better understanding of how asthma works could allow researchers to develop treatments that target specific proteins and pathways. But success is probably some way off. The immune system is a complex network of interactions. If a single element is removed, the effects on the whole system may be far-reaching – with more knowledge of how the immune system works it may be possible to avoid these unwanted effects and come up with an effective treatment of asthma in all its forms.

Barry Kay is director of the Department of Allergy and Clinical Immunology at the National Heart and Lung Institute, London.

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Who suffers from asthma?

No one knows what it is, at the cellular or molecular level, that makes the airways of asthmatic people different from those of normal individuals. One of the few clues comes from Stephen Holgate and colleagues of the University of Southampton, who have found evidence that asthma sufferers have a defect in the cement or matrix proteins that bind the epithelial cells lining the airways to the underlying structures. This causes the epithelial cells to be-come detached, upsetting the balance of the local immune mechanisms, and allowing allergens to penetrate more easily and expose irritant receptors.

The trigger that initiates the condition we know as asthma – as opposed to an ‘asthmatic attack’ in an established sufferer – is probably something that causes injury to the lung lining. Possible culprits include viral infection, high exposure to allergy-provoking substances (allergens) or even the direct toxic effect of pollutants. Certain risk factors are known to increase an individual’s susceptibility to the onset of asthma – most notably, prolonged exposure to one or more of the triggers, and smoking, both active and passive. Genetic factors seem to be less important than environmental ones. For example, where one member of a pair of identical twins has asthma, the chance of his or her twin also having the disease is only 20 per cent. But there is certainly some genetic link in extrinsic asthma, because people with atopy – the hereditary predisposition to overproduce antibody in response to some allergens – are likely to suffer from extrinsic asthma as well as other allergic conditions such as hay fever and dermatitis.