Immunotherapy - teaching the immune system new tricks

Science writer, author of The Allergy Bible, and co-author of The Complete Guide to Food Allergy and Intolerance, Linda Gamlin investigates immunotherapy, a little used (in the UK) yet efficacious way to manage allergy.

The steam engine, as everyone knows, was a British invention. The earliest engines, for industrial use, were built in the 18th Century. They were gradually improved upon until, in the early 19th Century, the first steam trains began carrying passengers.

In 1830, a British politician, William Huskisson, was killed, run over by a train during a celebratory jaunt for dignitaries. (Everyone had been advised to stay on the trains while they stopped to refuel, but Huskisson stepped out onto the tracks to speak to the Duke of Wellington in another carriage, failing to notice the Rocket chugging towards him.) The news of this first railway fatality spread around the world, but far from deterring other countries from adopting trains, it actually helped to publicise this remarkable new means of transport.

Now - imagine this. Suppose the death of Huskisson had been regarded, by the British government of the day, not as an accident that could have been avoided with sensible precautions, but as a sign that all steam engines were extraordinarily dangerous things. Imagine if they had devised a set of stringent safety measures which put so many restrictions on steam power that, in effect, it was almost entirely banned from use. Imagine that, as a result, Britain had abandoned the industrial revolution. Meanwhile, other countries had decided to get on and build their own steam engines, and these had gone from strength to strength.

In Britain, long after the name of William Huskisson had been forgotten, the idea that steam engines were too dangerous to contemplate persisted, an unquestioned piece of shared wisdom. The evidence from other countries, that steam power could be harnessed safely, was simply ignored. Britain remained stubbornly in the age of the horse and cart.

Change the dates and the details and this is - very roughly - the history of immunotherapy for allergies in this country.

Immunotherapy - turning allergic reactions off at source by re-tuning the immune system - was first devised by two British medical researchers, Leonard Noon and John Freeman, in 1911. It gradually became more and more widely used, a steady expansion that has continued to this day in other countries. In the US, immunotherapy by injection has long been a standard and commonplace form of treatment (they call it 'allergy shots'). Most other Western countries that are afflicted by the allergy epidemic also use immunotherapy, either by mouth or by injection, as a routine treatment for difficult cases. Sensible precautions are taken, and the dangers are minimised.

In Britain, however, immunotherapy has been unavailable to most allergy sufferers for over 25 years. A friend of mine, who has such severe hayfever that he has difficulty running his busy shop in early summer (getting little or no relief from anti-histamines and other drugs), recently went to his GP to ask for treatment with Grazax. This is a new and particularly safe kind of immunotherapy for grass-pollen hayfever (more about it later). No, he was told, he couldn’t have it - because "it isn’t proven and anyway it's too risky".

How did this peculiar situation come about, that a useful medical treatment, originally devised in Britain, is now so hard to obtain here, and is so deeply mistrusted by our doctors?

Teaching the immune system to behave

To get to grips with this story, we need first to understand a little about how immunotherapy for allergies works. Immunotherapy is a kind of re-education programme for confused immune systems. An allergy arises in the first place because the person's immune system gets the wrong idea about a particular substance - 'the allergen'.

If someone has an allergy, then their immune system mistakenly sees the allergen concerned - grass pollen in my friend's case - as part of a nasty marauding microbe that must be defeated whatever the cost. When it encounters that allergen, the misguided immune system comes out with all guns blazing.

The objective of immunotherapy is to re-educate the immune system of the allergic person so that it no longer 'sees' the allergen as an enemy. The re-education process is a gradual one. In its traditional form, it starts with showing the immune system a very tiny amount of the allergen - for example by an injection just under the skin. Such a miniscule amount of the allergen is given that the immune system can’t get upset by it. Then after an interval (an hour, a day, a week - it varies) the immune system is given a slightly larger amount of the allergen. There is another wait, and then a little more of the allergen is offered. And so it goes on.

If the process works well, the amount of allergen gradually builds up and up, and the immune system is lulled into acceptance, taking the whole process very calmly. At the end of the process, it can tolerate quite a substantial amount of the allergen without trouble. At that point, the patient is considered to be 'desensitised' or 'hyposensitised'. (This state is not yet irreversible however, and monthly maintenance doses are needed for another 2-4 years to achieve a lasting tolerance.)

Problems arise if the immune system does not accept the gradual increases in the dose of allergen as calmly as it should. Sometimes one particular step up is a step too far, and the immune system goes on red alert again. With luck, the reaction may be relatively minor - a widespread rash known as urticaria, for example - in which case it is just a question of waiting for the symptoms to subside, lowering the dose the next time, and increasing more gradually thereafter.

Sometimes (very very rarely if immunotherapy is being done well) the reaction is much more severe than this. It can progress to anaphylactic shock and collapse. In those who already have asthma, a severe asthma attack can occur.

How we arrived at the immunotherapy 'Dark Ages'

During the 1970s and 1980s in Britain, immunotherapy was being given by GPs because of the lack of consultant allergists and specialised allergy departments in hospitals here - a continuing problem for British allergy patients. Most of the GPs hadn’t had enough training in giving immunotherapy and didn’t know how to minimise the risks. The rate at which the dose of allergen was increased was sometimes too fast. Elementary safety precautions were omitted - patients might be given an increased dose of allergen and allowed to leave the surgery immediately, even though they weren’t feeling great. Some suffered anaphylaxis or an asthma attack shortly afterwards, did not have an adrenaline auto-injector (Epipen) available, and were unable to get to hospital promptly. The consequences of this could be disastrous.

Between 1980 and 1986 there were, tragically, eleven deaths in Britain caused by immunotherapy. In response to these deaths, the Committee on the Safety of Medicines (CSM) introduced a set of stringent safeguards for immunotherapy. The new rules stated that nobody with asthma could have immunotherapy (since several who had died were asthmatics), that patients must always wait a full hour after each injection, and that the treatment could only be given where there was cardio-pulmonary resuscitation equipment available.

It was this last regulation that completely scuppered immunotherapy in this country, because only hospitals have that kind of equipment: this meant GPs couldn’t give the treatment any longer. Since very few hospitals had an allergy consultant or allergy clinic (even fewer than now), and these specialists were already so over-stretched, immunotherapy became a treatment that was rarely given at all. Someone with a severe allergy to bee or wasp venom - a potentially deadly allergy - might be lucky enough to get immunotherapy on the NHS, but even these patients could wait several anxious years to get the treatment.

In the 25 years since then, the lack of availability of immunotherapy has also led to a kind of Dark Ages in which there is massive ignorance of the whole topic. Many GPs, and other doctors without any training in allergy, don’t realise that this treatment was actually a British invention, or that it is used so commonly and so successfully in other countries.

Immunotherapy returns to Britain

The availability of immunotherapy in Britain is, at last, increasing - but only very slowly. We have a few more allergists and allergy clinics than before (though still not nearly enough - and their distribution is extremely patchy).

Some of the specialist allergy centres, such as the Paediatric Allergy Clinic at St Thomas's Hospital in London, now have quite extensive programmes of immunotherapy treatment. British allergists whose careers have included time in the US, such as Professor Gideon Lack, have helped to spearhead this renewed awareness of immunotherapy. Some of the younger generation of allergists are also carrying out scientific research on immunotherapy. The publicity that this research generates may slowly dispel the mistrust and ignorance of our GPs.

A very helpful development, aiding this process along, has been the introduction of immunotherapy treatments which, rather than being injected are either swallowed or allowed to dissolve under the tongue. Sub-lingual ('under the tongue') immunotherapy is proving especially popular. "This form of treatment is much safer, so it can be given at home," says Dr Adam Fox who runs a sub-lingual immunotherapy clinic for children at St Thomas's.

The sub-lingual immunotherapy technique was invented by a US doctor, back in the 1930s, but few doctors took it up in the US. Much later it was developed in Italy and then various other European countries, beginning in the 1990s. It is now used almost as frequently as injection immunotherapy in continental Europe. In the US, it is less popular and lacks government approval - probably because 'allergy shots' are such a strongly established tradition in the US.

Immunotherapy treatments that are swallowed, rather than dissolved under the tongue, have also been developed. This approach is particularly useful with food allergies (where injected immunotherapy has never worked very well). Again, it is Italian doctors who have been most active in developing this type of treatment - although a British allergist, Dr Andrew Clark of Addenbrooke’s Hospital in Cambridge, has recently become a key player in this field. His revolutionary treatment for youngsters with peanut allergy has received a great deal of publicity: more about this later.

Could immunotherapy help you or your child?

As an allergy patient (or parent of a patient), you will no doubt have two burning questions. Is immunotherapy likely to help? If 'yes', what chance is there of getting it?

The answers vary depending what kind of allergic condition you suffer from. To summarise very briefly:

Allergy to bee or wasp stings

Immunotherapy for sting allergy is given by injection. (There are trials going on with sub-lingual immunotherapy for venom allergy, but at the moment this is not available here.) This treatment is a real life-saver and life-changer: when given to people who have had severe systemic reactions (anaphylactic shock leading to collapse) in the past, 97% do not suffer systemic reactions to stings after immunotherapy. The other 3% have less severe reactions than before, which means their risk of dying from a sting is much reduced. Those figures are for wasp allergy: the success rate for bee allergy is not quite as impressive, but it is still very good.

This treatment is, in theory, available on the NHS for anyone who has had a severe reaction to a sting, except those who also have severe asthma or brittle asthma. It will help if you know whether you reacted to a bee or a wasp (keep the culprit if at all possible). Even then, the allergy has to be confirmed by a skin prick test or blood test. Children are not usually given immunotherapy because their reactions to stings tend to be less severe. You will need referral to an allergist by your GP, but you may have a struggle to get it, especially if you live in Scotland, where allergists are as rare as hen's teeth. Be prepared to ask and keep asking - the benefits are enormous.


Hayfever is a prime candidate for treatment with immunotherapy. It responds well to under-the-skin immunotherapy injections - this was the treatment originally devised by Noon and Freeman in 1911, and found to help those with hayfever. You are unlikely to be offered such treatment under the NHS in Britain.

Sub-lingual immunotherapy is not quite as good in terms of effectiveness but it comes close, and it is extremely safe. It is also much less bother, for both patient and doctor, than the injections.

Grazax - mentioned above - is a one-size-fits-all immunotherapy treatment for grass-pollen hayfever. It breaks with immunotherapy tradition in that there is no gradual increase in the dosage: the tablets that you dissolve under your tongue each day are all of the same strength. So how does it work? The thing to understand here is that the different entry points into the body (skin, nose, airways, eye, mouth, stomach etc) are each defended with a particular style of immune response. In some places, the emphasis is more on tolerating the items encountered than on taking umbrage and attacking. It seems that the area under the tongue has a bias towards easy-going toleration. So this is a good target for immunotherapy, and the desired result can be achieved even without the gradual step-by-step increase in dose.

The level of allergen in a Grazax tablet is actually very high compared to the first injections that would be used in traditional immunotherapy, and yet the risk of a systemic reaction is almost zero. There are local reactions within the mouth, such as itching and swelling, but anything more serious is very rare indeed, and has only ever occurred with the first dose (which must be taken under medical supervision in Britain). There have been no fatal reactions at all, which is why Grazax can be safely taken at home once you are past the first dose.

Another approach to sub-lingual immunotherapy uses drops placed under the tongue. With these, a gradually increasing dose can be given, in the traditional way. Most allergists prefer this approach, for much the same reason that drivers prefer manual cars to automatics: the doctor can be flexible and exercise skill and judgement. For instance, he or she can begin with a very low dose indeed for a highly sensitive patient, and can adapt the dosing regime as it goes along, giving a lower dose next time if there is a big local reaction to the one before.

Immunotherapy may not make your hayfever vanish entirely. For some sufferers it simply reduces the symptoms to a level where they are bearable. As one hayfever sufferer who responded well to Grazax puts it: "If one can barely go outside in mid June, no matter how many anti-histamines are consumed, imagine how you’d feel, if after a course of sub-lingual immunotherapy, those anti-histamines now actually worked, and your hayfever went from intolerable to manageable. In my case it disappeared completely [which it does in a proportion of patients]. Admittedly, on a really high pollen count day, out in the country, I do feel a tingle coming on - so I pop an anti-histamine, and then I’m OK. To me, that’s a complete liberation. Five years ago, I would have been incapacitated."

What are the chances of getting either of these treatments? In theory, your GP could prescribe Grazax for you, get you to take the first dose in the surgery, then let you continue taking the rest at home. You would not need a referral to an allergist. But your allergy to pollen would have to be proven first, with either a skin prick test (which few GPs can offer) or a blood test (which he or she can order). And you would only be given this treatment if you had tried all the other medical treatments available, and still had an intolerable level of symptoms.

That is the theory. In practice, you might seem to qualify but still be refused. Even if your GP is better informed about Grazax than the one my shopkeeper friend consulted, there is the problem of cost. Each Grazax tablet takes over £2 out of your GP's total budget, and you need to take them for 4 months before the pollen season begins (starting 2 months beforehand may work, but it may not). In effect, that means beginning at the end of January and going through to mid-August, and the cost per year approaches £500. (Some doctors think that Grazax should be taken year-round to be effective, which means a price tag of £800.)

A study from Spain showed that, in spite of these high costs, the use of sub-lingual immunotherapy was cost-effective overall for people with extreme hayfever.  In this study the costs of anti-histamines and other hayfever medicines, plus days lost from work in the pollen season, were all added up and compared with the cost of the immunotherapy.

One severely affected hayfever sufferer, who was dependent on depot steroid (Kenalog) injections to get through the pollen season, researched the possible side-effects of these injections. Having found that some quite alarming side-effects were possible, he used this as a lever to get his GP to prescribe Grazax. He found that it was necessary to take the battle up to the next level of responsibility, where funding decisions were made.


The ban on giving immunotherapy to anyone with asthma has been relaxed somewhat so that, for example, someone with insect sting allergy can now receive immunotherapy even though they also have (moderate) asthma. However, immunotherapy is still not seen - officially - as a suitable treatment for asthma per se. This is unfortunate because research in other countries shows that it can bring substantial benefits to patients. It can even alter the course of asthma in children, avoiding a worsening of the condition and damaging changes to the airways. In practice, a recent survey suggests that some allergists are in fact using immunotherapy for asthmatics with strong allergic responses.

Atopic eczema

Immunotherapy has, in the past, been considered of little value for atopic eczema: indeed, some research suggested that it could even make the eczema worse for certain patients. This may be explained by the fact that the immune reactions underlying atopic eczema are much more complex and varied than those of allergic conditions such as hayfever. In addition, a less robust skin structure is at least half the story for many atopic eczema patients.

More recently, researchers in Italy and Germany have suggested that immunotherapy against house dust mite could be useful in cases where someone with atopic eczema is highly sensitive to this allergen. The jury is still out on this. Even if it proves to be the case, it is very unlikely that immunotherapy for atopic eczema would become available in Britain in the forseeable future.

Food allergy

There is a type of food allergy that goes with hayfever and whose symptoms are relatively mild: usually just tingling and itching in the mouth. It is due to a cross-reaction between an allergen in the pollen and a very similar allergen in the food. The food most commonly responsible is fresh apple, but other fresh fruits may also be involved. This type of allergy can - for some sufferers - diminish markedly following immunotherapy for hayfever (that is, immunotherapy for the pollen, not for the food itself). Note, however, that an improvement isn’t guaranteed, and some people find that their reaction to fruit gets worse following immunotherapy.

The pollen usually involved in these responses is birch, not grass. There is no simple immunotherapy regime for birch pollen that a GP could prescribe and administer, unlike the situation with grass pollen allergy, so you would need a referral to an allergist.

Better known is the more dangerous type of food allergy, which can result in body-wide symptoms, collapse due to anaphylaxis, and even death. Children with this kind of allergy to egg or milk have long been the focus of efforts by Italian doctors to induce desensitisation, using gradually increasing doses of the food. These doses, beginning with a miniscule amount, are given by mouth and swallowed. Promising results have been obtained by such methods but this treatment isn’t yet available in Britain.

More recently, Dr Andrew Clark of Addenbrooke’s Hospital in Cambridge, experimented with such a desensitisation programme for teenagers with peanut allergy. He has achieved notable success and, through his extremely careful approach, no life-threatening reactions. The treatment doesn’t allow patients to eat freely, but it does protect them from having severe and potentially fatal responses to slight traces of peanut. This allows them to live more normal lives. Once the programme is complete, he has found that, in order to maintain the desensitised state, it is necessary for patients to continue eating a few peanuts every day.

Larger scale trials are in progress, and it is worth asking your doctor if you can be referred to Addenbrooke’s Hospital to take part in such a trial. Dr Clark believes that this will, one day, be a standard treatment for peanut allergy, but says "Realistically, it will some time before it is available anywhere other than Cambridge."

In conclusion, immunotherapy is a useful but expensive treatment. It isn’t a miracle cure, except for a few lucky individuals, but it can make symptoms a great deal less troublesome and be life-changing for those with severe allergy. If you feel that you or your child might benefit from immunotherapy, ask your GP, or ask your allergist (if you are seeing one) - and be prepared to keep on asking!

First published January 2013


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