Allergy and Your Immune System
`The summer used to be such a miserable time for me because I’m allergic to grass pollen. For most of
my life I have had dreadful hayfever, and my asthma would get worse during the summer as well.
Antihistamines knocked me for six, and although there were nose drops that helped a little, they
certainly did not resolve the problem completely. Exam time was always a nightmare when I was a student
- then, as now, it coincided exactly with the pollen season.’
‘Getting a job in Chicago was a turning point in my health. My colleagues were amazed to see me
snuffling through the summer and just accepting that nothing could be done to improve matters. The
whole approach to treating allergies is different there. Eventually someone marched me off to see her
allergist, who said that I should have “allergy shots” and that my health insurance would cover it. The
process was very time-consuming at first, and it took a while to work, but the change is remarkable.
I’ve never regretted having the treatment. Summer is a time I can actually enjoy now.’
Not everyone responds this well to immunotherapy, but for those allergy sufferers who do benefit, this
is an excellent treatment. It tackles allergies right at their source, by teaching the immune system to
react differently to the allergen.
Also known as Specific Immunotherapy (SIT), Incremental Immunotherapy (11T) or simply as
hyposensitisation, this form of treatment was devised by two English medical researchers, Leonard Noon
and John Freeman, who reported their successes with hayfever patients in 1911. Ironically, their
treatment is now less readily available in Britain than in any other industrialised nation. Only a
small minority of British allergy patients receive immunotherapy. The cause of this strange situation
is a ruling made in 1986 by the Committee on the Safety of Medicines (CSM). This states that
immunotherapy must only be given where there is resuscitation equipment available, and that all
patients must wait for an hour after each injection, in case of
side effects. In addition, immunotherapy cannot be used for severe asthma.
The requirement for resuscitation equipment rules out most GP surgeries, and this effectively puts
immunotherapy beyond the reach of many allergic individuals in Britain, owing to the extreme shortage
of allergists and hospital allergy clinics (see p. 89). (In the past, the lack of allergy specialists
meant that most immunotherapy in Britain was given by GPs.)
The CSM ruling was triggered by a number of deaths due to immunotherapy: there were eleven fatalities
between 1980 and 1986, with five of these in the eighteen months just before the report. But almost all
these deaths were due to very basic errors in the way the injections were given – tragic as the deaths
were, the official response to them was inappropriate. Fatal reactions to immunotherapy can be avoided
with close attention to ordinary safeguards (see p. 166-7).
Allergen immunotherapy is still freely available elsewhere in the world, and is regarded as a key part
of allergy treatment. Britain is now out of step with all other developed countries, and most doctors
feel that British restrictions are far too strict.
There are hopes that this situation may change within the next few years, and that more allergy
sufferers may be able to take advantage of this valuable treatment. This could be achieved, in part, by
investing more National Health Service money in allergy clinics and allergy specialists. In addition,
there should be a relaxation of the regulations, so that properly trained GPs can give immunotherapy to
patients who are not at high risk of a fatal reaction. For people whose lives are affected by
allergies, the reintroduction of this treatment (with appropriate safeguards) would be a huge boon.
The uses of immunotherapy
Immunotherapy is mainly used for airborne allergens such as pollen, house-dust mite and mould spores.
Allergies to animals can also be treated with immunotherapy, but the treatment cannot work miracles –
if a cat-allergic person decides to keep the cat, the high dose of allergen inhaled every day limits
the impact of immunotherapy treatment.
People with straightforward allergic reactions affecting the nose and eyes (allergic rhinitis and
conjunctivitis) respond well to immunotherapy. In patients with hayfever, for example, the success rate
(patients showing some degree of improvement) is about 80-90%. When nasal allergies are complicated by
chronic sinusitis or nasal polyps, the chance of success is a little lower.
Some studies of the long-term effects of immunotherapy suggest that, if it is given to children with
hayfever or perennial rhinitis, those children are less likely to develop asthma.
The benefits of using immunotherapy to treat established asthma are less certain. Asthma is a more
complex disease than hayfever, and allergies are only one factor among many (see p. 36), which may
limit the impact that immunotherapy can make. Experience suggests that immunotherapy can be a great
help for an asthmatic with a strong allergic reaction to a single airborne allergen, such as grass
pollen or house-dust mite, but not for other asthmatics. Asthmatics with aspirin sensitivity or chronic
sinusitis are unlikely to benefit.
The value of immunotherapy to children with asthma is a subject of great debate among doctors in the
United States. Some studies suggest that it is of little real benefit, while others are more positive.
One interesting study, that followed asthmatic children for 15 years or more, found that if they were
given a full five-year course of immunotherapy when young, they tended to have fewer asthma symptoms
and need less medication in their late teens and early twenties.
Chronic urticaria (nettle rash) is occasionally due to airborne allergens, in which case immunotherapy
may help. However, immunotherapy is not recommended for atopic eczema. When people with both eczema and
rhinitis try immunotherapy for their nasal allergies, some find that their eczema gets worse.
Insect-sting allergy is a prime candidate for immunotherapy (see pp. 167-8) but food allergy is a
different matter, and is not treated with immunotherapy at present (see p. 168).
Who can get immunotherapy?
As a result of the CSM ruling (see p. 164) remarkably few allergy sufferers in Britain receive
immunotherapy.
Those with insect-sting allergy, who have suffered anaphylaxis (see p. 58), are the most likely to be
offered this treatment. However, even with this frightening and life-threatening problem, which can be
treated with almost 100% success by immunotherapy (see p. 167-8), such treatment is not automatically
available.
A few people with severe hayfever that does not respond well to drug treatment may also be given
immunotherapy. It is worth asking your doctor about such treatment if you feel you would benefit.
How immunotherapy works
Immunotherapy consists of a series of small injections, just under the skin. The liquid that is
injected contains an extract of the offending allergen, for example house-dust mite. The injections are
given at regular intervals, usually once a week, although other schedules are possible (see p. 167-8).
At the outset, a very dilute version of the allergen extract is used, way below the threshold for an
allergic reaction. People who seem highly sensitive, on the basis of their skin tests, start on an
extract that is even more dilute.
For the next injection, a slightly higher concentration of the allergen extract is used, and the
concentration goes on increasing with each successive injection. The idea is to habituate the immune
system to the offending allergen, by very gradually raising the dose. Eventually, when the dose reaches
a level which generally gives beneficial effects, no further increases are made.
If an allergy sufferer reacts badly to immunotherapy injections (see p. 166) on several successive
occasions, the dose may be levelled off before the ideal maximum dose is reached. However, a good
allergist will persist for some time in trying to increase the dose because stopping at a lower level
often results in the treatment being ineffective.
The first stage of immunotherapy, when the concentration of allergen is being increased week by week,
is referred to as the build-up stage. The second stage, when the dose is being kept at the same level,
is called maintenance therapy, and the dose used is the maintenance dose.
There is sometimes an obvious improvement by the time the build-up stage is complete, but not always.
The benefits of the treatment generally appear within six months of reaching the maintenance dose, but
some people have to wait a year or even two before things improve. As the immunotherapy begins to take
effect, symptoms decline and there is often less need for drugs.
A great deal of research effort has gone into finding out what lies behind these changes – in other
words, what is actually happening to the immune system when immunotherapy is effective. The answer is
that a surprising number of different changes may occur and no two allergy sufferers react to
immunotherapy in quite the same way. Frequently there is a shift in the kinds of antibodies the body
produces against the offending allergen. Levels of IgG antibodies (which help to block the allergic
reaction) go up, while levels of the allergy antibody, IgE, tend to stabilise and eventually go down.
The numbers of mast cells (see box on p. 12) may also decline, and they can become less responsive to
the allergen. The balance of power between Th1 cells and Th2 cells may also shift, with the pro-allergy
Th2 cells (see p. 11) becoming less influential.
What can go wrong
The secret of safe immunotherapy is to go at exactly the right speed for the immune system of the
individual being treated. The doctor should look for feedback from the immune system – signs that show
how well it is coping with the steadily increasing dose of allergen – and use these to pace the
immunotherapy schedule.
Going too fast – getting ahead of the immune system’s ability to cope – is hazardous. A major allergic
reaction, called anaphylaxis (see p. 58), can occur, and this is the cause of deaths during
immunotherapy. However, as long as there is injectable adrenaline (see p. 150) and resuscitation
equipment available, even such an extreme crisis can be dealt with safely.
Serious reactions to immunotherapy usually occur:
• during the initial build-up phase; maintenance therapy is much safer
• during the pollen season, for those with pollen allergy
• when a new vial of allergen extract is first being used, because of variations in concentration
(see p. 168-9).
Those most vulnerable to severe reactions are:
• people with asthma, especially severe or unstable asthma
• those who have experienced systemic allergic reactions in the past
• anyone who appears to be extremely allergic, on the basis of skin tests
• anyone taking beta-Mockers (see box on p. 150).
With care, these fatalities can be avoided. Patients who are given immunotherapy can ensure their own
safety by being well informed about the procedure (see p. 167).
The timing of immunotherapy
There are various different approaches to the timing of immurotherapy. The basic method (which has a
good safety record in the United States where it is very commonly used) starts with injections once a
week. After the maintenance dose has been reached, maintenance injections are given once every 2-4
weeks. The frequency of these may be increased during the pollen season, for people with pollen
allergies.
It is the regularity of the injection schedule that gradually creates, and then sustains, immune
tolerance, so the treatment is only of value to patients who can reliably keep their appointments.
When immunotherapy is successful, it can eventually be discontinued without any reappearance of the
allergic reaction. It usually takes 4-5 years of regular therapy, from the time of the first injection,
to get to this point. The benefits then persist for many years, perhaps indefinitely in some people,
even without any further injections.
Rush immunotherapy
Trying to speed up the process of immunotherapy greatly increases the risk of a severe reaction
(anaphylaxis). However, there are some situations where fast results are needed, and in such cases rush
immunotherapy, also called accelerated immunotherapy, may be used.
During the build-up stage of rush immunotherapy, injections are given every day, or even several times
a day. All the usual safety procedures (see below) are observed with particular care, to reduce the
chance of a severe reaction.
In semi-rush immunotherapy, the build-up injections are given twice a week, and the risks are lower
than with daily injections, but still higher than with weekly injections.
Minimising the risks
If you are lucky enough to be offered immunotherapy treatment under the National Health Service, you
should not feel concerned about accepting the offer. There is very little risk of a bad reaction
because safety procedures are now so stringent.
To minimise the risk of suffering a severe reaction, the doctor will ask you, at each visit, about any
reactions that occurred after your previous injection. Reactions might include redness, itching or
swelling around the injection site, or (more seriously) symptoms elsewhere on the body, such as nettle
rash (urticaria), itchy skin, sneezing, a runny nose, red or itchy eyes, tightness in the throat or
chest, coughing or wheezing. Always make a note of such symptoms, so that you don’t forget to mention
them at the next visit. This is crucially important, as such reactions can indicate that the immune
system is being hurried along too fast.
The doctor will also ask if you have an infection of any kind, as this can alter your reaction. You
should also tell the doctor about any new medicines being taken, as some, such as betablockers (see box
on p. 150), can make a bad reaction to the injection more likely to occur.
Asthmatics can expect the doctor to ask about current asthma symptoms, and to check their peak flow
both before and after an injection. If there are any symptoms, or if the peak flow is less than 70% of
the best-ever value, the injection won’t be given.
Severe reactions can sometimes begin several hours after the injection, so stay within reach of a phone
for about 24 hours. Among United States allergists (who don’t require their patients to wait after the
injection for more than 20-30 minutes) there are some who believe that everyone undergoing
immunotherapy should carry an adrenaline (epinephrine) auto-injector (see p. 150) on the day an
injection has been given, for use in the event of a severe reaction. Anyone who has suffered
anaphylaxis in response to an insect sting will probably have an adrenaline auto-injector anyway, and
this can certainly be used to treat anaphylaxis following immunotherapy. Note, however, that using the
adrenaline is just the first step in treating anaphylaxis (see p. 98) and you must then go back to your
allergist, or to the nearest hospital emergency department, without any delay.
It is sensible to avoid exercise for two hours after an injection. Be extra-cautious during the pollen
season if you are receiving immunotherapy for pollen allergies.
Immunotherapy for insect-sting allergy
`Our daughter has had two really bad reactions from being stung by a wasp. After the second one, the
doctor at the accident and emergency department told us that she nearly died. We got so anxious about
it that we worried every time we left the house in the summer, and it was even worse if she went out
without us. My wife got so upset about it that she wasn’t sleeping well. It was affecting the whole
family badly.
‘Then we heard about desensitisation treatment, and asked our GP, but he said he couldn’t do it.
According to him, they might be able to do it at the hospital, but it might not work, and it was risky
too. We accepted that at first, but then I started doing some research on the Internet, and discovered
that in America and Germany this treatment is absolutely standard – someone like our daughter would
automatically be given it. We felt very angry when we found this out, and went back to the doctor.
Eventually Ann was referred to the allergy department at a hospital, and now she is getting this
desensitisation treatment. I’m pleased about that, obviously, but I still think it shouldn’t have been
such a fight to get it.’
Immunotherapy provides highly effective protection for those with insect-sting allergy, and should be
given to anyone who has had a severe systemic reaction (see p. 60). Some United States allergists also
recommend it for adults who have had a cutaneous systemic reaction (see p. 60), on the basis that they
may well progress to a severe systemic reaction with the next sting.
Studies of people who have suffered severe systemic reactions, and are then treated with immunotherapy,
show that 97% have no systemic reaction to future insect stings. For the 3% who are not fully
protected, the severity of the reaction is much reduced and far less likely to be life-threatening. In
other words, this is an excellent treatment which can save lives.
Targeting the treatment
Choosing the right venom for immunotherapy can sometimes be difficult. Not everyone with insect-sting
allergy sees the insect that caused the reaction. Skin tests may not give the answer either, because
there are often positive reactions to several different venoms. Some of these may be false positives
(see box on p. 91) and it is impossible for the allergist to say which one(s) are actually relevant.
Most allergists will recommend immunotherapy for all of them, using a mixture of venom extracts.
Where the guilty insect was seen and identified, but other venoms also give positive skin tests, a more
difficult decision has to be made. Many allergists carry out immunotherapy for all the venoms that gave
a positive skin test, on a ‘better safe than sorry’ basis. Since there are cross-reactions between
venoms (see box on p. 113), there is some sense in this. Other allergists just give immunotherapy for
the insect that did the deed.
Will immunotherapy against one insect protect against a related insect? With two closely related
insects such as wasps and hornets, which have many allergens in common, it might do – but there is no
guarantee. The problem is that, as well as the shared allergens, each venom also has its own unique
ingredients. It’s impossible to say, with the kind of tests available at present, if an allergic
reaction was to shared allergens or unique ones. So immunotherapy against wasp venom may give
protection against hornet venom, but it will not necessarily do so – and vice versa.
In the case of bumblebee allergy (seen almost exclusively in those, such as horticulturalists, whose
work involves handling bumblebees) a more definite answer can be given – honeybee immunotherapy does
not work. Immunotherapy with bumblebee venom does work, fortunately. The bumblebee extract has to be
obtained from specialist sources.
Injections are given weekly during the build-up phase, unless protection is needed urgently, as with
work-related sting allergy, in which case rush immunotherapy may be used. Once the maximum dose has
been reached, a maintenance injection is needed every four weeks. After a year, this maintenance dose
can be given every 6-8 weeks.
After 3-5 years of immunotherapy, skin tests with insect venoms are usually tried again. If the results
are negative, the immunotherapy will stop. Research now shows that, even if skin tests are still
positive when immunotherapy ends, there’s an 8090% chance that no systemic reaction will occur to
future stings. Some people are not reassured by this, and prefer to continue with immunotherapy for
their own peace of mind. Indeed, research shows that a near-fatal systemic reaction has a long-lasting
psychological impact, and that many people continue to feel anxious despite completing immunotherapy
and reacting negatively to skin tests.
At one time, challenge stings with live insects were given to check whether immunotherapy had actually
worked. Few doctors do this now, but your allergist may be prepared to do a challenge test if you ask.
Adrenaline and resuscitation equipment would be available if a challenge test were used, so any severe
reaction could be dealt with promptly and effectively. The fact that the psychological consequences of
insect-sting allergy are so persistent suggests that challenge tests with live insects may have a
particular value, in demonstrating that immunotherapy has worked. Challenge tests are also helpful for
those who work with stinging insects, such as honeybees and bumblebees, and who need to be sure that
they can go back to work safely.
Immunotherapy for food allergy?
Attempts to use standard immunotherapy for food allergy have been made repeatedly, but without success.
The process of giving the injections is nerve-racking because of the constant risk of a severe
reaction. The risks prevent the dose of allergen being increased very much, so the beneficial effects
are small. While there may be some reduction insensitivity, it is not enough – or not reliable enough –
to be of any practical value.
What doctors are aiming for here, incidentally, is simply to protect against the effects of
accidentally eating a tiny amount of the food – no one is expecting that someone with peanut allergy
will be able to eat peanut butter sandwiches as a result.
Some of the new developments in immunotherapy may be useful for food allergy, as described in the next
section.
The future of immunotherapy
Many different research teams are working on ways of improving immunotherapy – making it more
effective, safer to give, and less time-consuming.
One approach involves altering the allergen, so that it only interacts with those parts of the immune
system whose job is to control allergic reactions (and therefore bring about tolerance). The changes
made to the allergen are designed to make it ‘invisible’ to the parts of the immune system that
actually attack the allergen. The idea is to inject something that can’t cause a bad reaction, and is
therefore 100% safe.
The modified allergens are called allergoids. Another term often used is peptide immunotherapy – this
describes a technique in which the allergens are chopped up into small pieces to make them safe
(allergens are proteins, and a fragment of a protein is called a peptide).
Already, researchers in Germany have made an allergoid from birch pollen that can reduce hayfever
symptoms with a series of just seven injections given before the pollen season.
Meanwhile, a research team in London is working on peptides made from cat allergen, with encouraging
results so far. In a group of asthmatics who were allergic to cats, a series of 4-10 injections, over a
period of 2-8 weeks, produced benefits in about half those treated. The researchers believe that they
can improve on this and help the majority of people with cat allergy, at least enough to survive
temporary exposure to cat allergen (when visiting cat-owning friends, for example). They hope to refine
the treatment sufficiently to enable some cat-allergic people to keep their pet, rather than finding it
a new home. This is a relatively safe treatment that might be given by a GP, rather than only by
specialists. The research team hopes the treatment will be available by about 2009.
Could this kind of technique work for food allergy? Doctors believe that it can, and a great deal of
research work is being done, in both Britain and the United States. A major focus of this effort is
peanut allergy, since this puts so many young lives at risk. Even if the research is successful, It
will be several years before such treatments become available.
Researchers are also working hard to produce standardised allergen extracts – in other words, allergen
extracts that always contain a standard amount of the allergen. The aim is not only to reduce the
number of treatment failures (which can occur if the extract does not contain enough allergen) but also
to avoid mishaps when a new vial of allergen extract is used (differences in strength, between one vial
and another, are sometimes a cause of anaphylactic reactions).
Standardisation is difficult, because the starting materials –skin particles from horses, for example,
or dust-mite droppings –are natural materials and therefore variable. Some samples contain far more of
a particular allergenic ingredient than others.
One way around this problem is to develop accurate methods of measuring the amount of allergen in the
extract. Another approach is to abandon the whole business of making extracts, and produce allergens
artificially, in a laboratory. This is done by inserting the gene for the allergen – the gene for the
Der p1 allergen of house-dust mite, for example – into bacteria. These bacteria then act as production
units, manufacturing large amounts of the allergen every day. With this high-tech approach, the exact
content of the allergen preparations can be controlled.
These high-tech allergen preparations are extremely pure, and therefore very effective – as long as the
person receiving immunotherapy really is sensitised to the particular allergen that is included.
Unfortunately, most natural allergenic materials contain two, three or even more separate allergens. In
house-dust mite droppings, for example, while Der p1 is the allergen that affects most people, there is
also an allergen called Der p2, and a few people are more sensitive to this than to Der pl.
Artificially produced allergen preparations usually include the main allergen only. For the minority of
people who are more severely allergic to one of the other allergens, this extract will not work.
Eventually this problem will no doubt be circumvented by means of more precise skin testing before
immunotherapy begins – skin tests with individual allergens, rather than with allergen extract
containing a mix of allergens.
A third approach is to change from injections to oral immunotherapy – giving the allergen extracts by
mouth. The best results are obtained when the allergen is held under the tongue for a while and then
swallowed. This is known as Sub-lingual immunotherapy or SLIT, and has become very popular in Italy and
France, where it is a common treatment for hayfever. A recent pilot trial among GPs in Britain suggests
that it may be useful, but is not a miracle cure. Overall, the group treated with SLIT had fewer
symptoms during the pollen season, but antihistamines were still needed. There is some evidence from
Italy that SLIT might reduce the likelihood of children with hayfever going on to develop asthma, and
reduce the chance of new sensitivities.
Side effects are unusual with this treatment, and those that do occur are mostly mild – itching in the
mouth, for example. The treatment is safe enough for routine use in children.
Might oral immunotherapy work for food allergy? Other Italian studies suggest that it could. The
objective of these studies is to reduce the risk to children with cow’s-milk allergy from accidental
encounters with ‘hidden milk’ in prepared food or drink. The immunotherapy treatment begins with
miniscule amounts of milk – the doctors start with a single drop diluted in water, each day for a week
– and increase the dose extremely slowly. Antihistamines are given to minimise the risk of a reaction.
The whole process requires enormous patience, but after seven months, the majority of the children
involved can tolerate some milk – between three tablespoonfuls and a small cupful each day.
This is a very encouraging study that should be repeated by doctors in Britain. Because of the risks of
anaphylaxis – which can, of course, be fatal – it does require full medical supervision, and you should
not attempt it at home. Whether this method would work for allergens other than milk is something that
nobody has yet investigated.
A great many other approaches to immunotherapy are currently being tried for food allergy. Many of the
new techniques are highly experimental, and some show great promise, but it will be many years before
they are in use.
One innovation that is closer to being in general use in the United States involves giving the anti-IgE
drug omalizumab (see p. 149) alongside immunotherapy injections. The drug maximises the benefits from
the immunotherapy, and may make the build-up stage (see p. 165) safer, by lowering the risk of
anaphylaxis. For British allergy sufferers, who cannot yet get omalizumab, and whose chances of getting
immunotherapy are vanishingly small, it may seem unkind even to mention such treatments, but we can
only hope that things will improve here in the near future. You might take some comfort from the
thought that, by the time immunotherapy is available again in Britain, there will be a whole host of
highly effective new techniques available for doctors to try.
All the methods described above are forms of specific immunotherapy – they treat an allergy to dust
mites or to grass pollen or some other specific allergen.
A far more radical and ambitious approach to immunotherapy is now the aim of some medical researchers:
blocking the tendency to allergies as a whole.The underlying idea here is to reverse the basic shift in
the immune response, from Th1 cells to Th2 cells. It is this shift to Th2 cells which produces the
allergic tendency (see pp. 11 –13).
Some interesting findings have already been made in this area, including the surprising discovery that
the balance of Th1 cells and Th2 cells can be adjusted even in people with longstanding allergies.
Inspired by discoveries about hygiene and allergy (see p. 21), British researchers have made a vaccine
containing inactivated cells of a harmless bacterium found in the soil, Mycobacterium vaccae. This is
given as a single injection just under the surface of the skin. It has been used for adult patients
with asthma, and for children with severe atopic eczema, with some improvement in both groups. If the
treatment proves as useful as the preliminary studies suggest, this could be a common treatment in a
few years’ time.
