Anthony J. Frew, MD, FRCP
Brighton, United Kingdom
Specific immunotherapy (SIT) involves the administration of
allergen extracts to achieve clinical tolerance of those allergens
that cause symptoms in patients with allergic conditions.
Immunotherapy is effective in patients with mild forms of
allergic disease and also in those who do not respond well to
standard drug therapy. Most SIT is given by means of injection,
but there is increasing interest in performing SIT through the
sublingual route. SIT remains the treatment of choice for
patients with systemic allergic reactions to wasp and bee stings
and should be considered as an option in patients with allergic
rhinitis, asthma, or both. SIT can modify the course of allergic
disease by reducing the risk of new allergic sensitizations and
inhibiting the development of clinical asthma in children treated
for allergic rhinitis. The precise mechanisms responsible for the
beneficial effects of SITremain a matter of research and debate.
An effect on regulatory T cells seems most probable and is
associated with switching of allergen-specific B cells toward
IgG4 production. Few direct comparisons of SIT and drug
therapy have been made. Existing data suggest that the effects of
SIT take longer to develop, but once established, SIT achieves
long-lasting relief of allergic symptoms, whereas the benefits of
drugs only last as long as they are continued. (J Allergy Clin
Key words: Immunotherapy, immunomodulation, rhinitis, asthma,
T cell, B cell, IgE, IgG, sublingual
In allergen specific immunotherapy (SIT) allergen extracts are
to be carefully assessed, with particular regard to allergic triggers.
In addition, because the course of treatment is lengthy and rela-
tively expensive, there must also be an assessment of the risks
and costs compared with those of symptomatic treatment with an-
tihistamines and topical corticosteroids.
Immunotherapy was first developed at St Mary’s Hospital
ciples described by Noon and Freeman remain valid today. How-
ever,over theyears,SIT hasevolvedindifferentways indifferent
centers and in different countries, leading tovaried treatment reg-
imens and distinct philosophic approaches to the therapy. Indeed,
much of the early literature on SIT is striking for its clinical em-
piricism and the lack of the type of objective evidence that would
be required if this technique were to be introduced nowadays.
tific practice against allergists, even though the same point could
be made about a whole range of medical practice. In recent years,
firmed the effectiveness of SIT and have validated several of the
there is still a range of clinical practice and a variety of strongly
held opinion about the best way to perform SIT. In particular,
American allergists tend to treat for all sensitivities identified as
clinically relevant on skin testing using mixtures of extracts pre-
pared from bulk vials, whereas in Europe patients are normally
only treated with a single allergen, which is supplied direct
from the manufacturer. Mixed allergen extracts are available
and used in some parts of Europe but only as custom mixes
from manufacturers. Another difference in clinical practice is
that allergen extracts used in the United States are prepared in
the allergist’s office, whereas those used in Europe are usually
supplied by the manufacturer in their final form. European ex-
tracts are dialyzed to remove low-molecular-weight components
and standardized according to their ability to elicit a wheal. In the
United States extracts might not be dialyzed; although ragweed
and cat extracts are standardized in terms of major allergen con-
tent, most extracts are standardized by their ability to elicit ery-
thema rather than wheal. However, at the end of the day, the
ences are in the details.
or maintenance dose is achieved. Maintenance injections are then
given at 4- to 6-week intervals for 3 to 5 years. The updosing
phase is generally given as a series of weekly injections, but
several alternative induction regimens have been tried, some
giving several doses on each day and then waiting a week before
giving a further series of injections (cluster protocol), whereas
others give the whole series of incremental injections in a single
risk of adverse reactions, which are much more common than in
conventional or cluster protocols. On the other hand, full
EPD: Enzyme-potentiated desensitization
SIT: Specific immunotherapy
SLIT: Sublingual immunotherapy
VIT: Venom immunotherapy
From the Department of Respiratory Medicine, Brighton & Sussex Medical School,
Brighton, United Kingdom.
Disclosure of potential conflict of interest: A. J. Frew is on the Advisory Board for
Allergopharma and Stallergenes; gives lectures for MSD, Schering-Plough, and
Novartis; gives lectures and is on the Advisory Board for ALK-Abello ´, UK; has
received research support from Allergy Therapeutics, Ltd, and ARTU biological NV;
has provided expert witness testimony on the topic of antihistamine patents; is on the
Executive Committee for the European Academy of Allergy and Clinical Immunol-
ogy; and is a Council Member for the British Society for Allergy and Clinical
Received for publication August 13, 2009; revised October 11, 2009; accepted for pub-
lication October 14, 2009.
Reprint requests: Anthony J. Frew, MD, FRCP, Department of Respiratory Medicine,
Brighton General Hospital, Brighton, United Kingdom BN2 3EW. E-mail: anthony.
? 2010 American Academy of Allergy, Asthma & Immunology
protection against anaphylaxis induced by Hymenoptera stings
with the conventional regimen.
MECHANISMS OF IMMUNOTHERAPY
The primary reason for studying the mechanisms of SIT is to
seek out the element or elements that are biologically important
and hence devise new forms of immunotherapy that might
improve efficacy, increase safety margins, shorten treatment
courses, or achieve more durable results. Several mechanisms
have been proposed to explain the beneficial effects of immuno-
therapy (Table I). Whether administered by means of injection or
sublingually, SIT induces changes in T-cell and antibody re-
sponses. The challenge for clinical scientists has been to work
out which of the observed changes drive the clinical benefit and
which are just epiphenomena. Allergen-specific IgE levels in-
crease temporarily during the initial phase of SIT but fall back
to pretreatment levels during maintenance therapy.2The immedi-
ate wheal-and-flare response to skin testing usually reduces dur-
ing the initial phases of SIT, but this effect is relatively small
compared with the degree of clinical benefit. In contrast, the
late-phase responsetoskintesting isvirtually abolishedafter suc-
cessful SIT. Similar patterns are observed for late-phase
cific IgG antibodies, particularly antibodies of the IgG4 subclass.
At one time, it was believed that these antibodies might intercept
the allergenic particles at the mucosal surface and ‘‘block’’ the al-
lergicresponse. Currentopinionis against this,partly becausethe
increase in IgG levels follows rather than precedes the onset of
clinical benefitand partlybecause manymast cells areon the mu-
cosal surfaces and therefore meet allergen before antibodies can
interpose themselves. Moreover, there is a poor correlation be-
In most studies the IgG level correlates better with the dose of al-
lergen that has been given rather than with the degree of protec-
tion achieved. That said, there has been a recent resurgence of
interest in a possible inhibitory role of specific IgG antibodies
in grass pollen immunotherapy.4In particular, the time course
fering with IgE-dependent cytokine secretion from mast cells or
facilitated antigen presentation to T cells.
SITalso induces changes in allergen-specific T-cell responses.
In nasal and skin allergen challenge models, successful SIT is
accompanied by a reduction in T-cell and eosinophil recruitment
TH1 and TH2 cytokine expression in the allergen-challenged site.
TH2 cytokine expression is not affected, but there is an increased
proportion of T cells expressing the TH1 cytokines IL-2, IFN-g,
and IL-12.5-7After venom SIT, there is induction of allergen-spe-
cific CD41regulatory T cells that express CD25, forkhead box
ilar findings have also been reported after SITwith inhalant aller-
gens.10IL-10 has a complex series of actions on the immune
lergen-specific IgG4 antibodies, which probably explains the
IgG4 response to SIT. If the IL-10 effect on T cells is what mat-
ters, then the IgG4 response should perhaps be viewed as a surro-
gate marker of IL-10 induction rather than the beneficial
mechanism of SIT.11Overall,it is clear that SIT has a modulatory
effect on allergen-specific T cells, and it seems that this is why
clinical and late-phase responses are attenuated without suppres-
sion of allergen-specific antibody levels or immediate allergic
SIT for venom hypersensitivity
Anaphylaxis to Hymenoptera venom is relatively rare but can
be fatal. Venom-specific IgE antibodies are found in 30% to 40%
of all adults for a few months after a sting, but these usually
disappear in a few months. This response is related to the total
serum IgE level and the patient’s IgE response to inhalant
allergens. Some unlucky subjects react more vigorously with
high concentrations of venom-specific antibodies, which can
persist for many years without further exposure to stings. This
group of patients are at risk of anaphylaxis to subsequent stings,
and a small number die from anaphylaxis each year. Precise
figures are hard to come by, but a figure of at least 40 deaths per
year in the United States has been cited. Additional sting-related
deaths may have occured in persons reported to have died of
The purpose of venom immunotherapy (VIT) is 2-fold: to
reduce the risk of fatality and to improve the patient’s quality of
life by allowing him or her to go out and work or play without
the relatively small number of fatalities, the main effect of VITis
on a person’s quality of life. The decision to proceed with VIT is
based on a careful assessment of the patient, as well as an
understanding of the natural history of venom allergy.13Patients
who have experienced systemic symptoms after a sting are at
much greater risk of anaphylaxis on subsequent stings compared
with patients who have only had large local reactions. The fre-
quency of systemic reactions to stings in children and adults
the risk in patients with a previous systemic reaction is between
30%and 70%.In general, childrenare less at risk ofrepeated sys-
temic reactions, as are those with a history of milder reactions.
With time, the risk of a systemic reaction decreases: by 10 years
after a previous systemic response, the risk is about 15% com-
pared with the general population’s risk of 2% to 3%. Occupa-
tional and geographic factors that might affect the likelihood of
future stings should also be considered. Bee stings are much
more common in beekeepers, their families, and their neighbors.
For most persons, wasp stings are sporadic, but they are an occu-
pational hazard for bakers, greengrocers, gardeners, tree sur-
geons, for example. Other factors to consider are the potential
risks of emergency treatment with epinephrine and the various
medical contraindications to SIT (see below).
Desensitization with venom accelerates the rate at which the
risk decreases and rapidly provides protection against field and
laboratory stings. After completing VIT, there is a residual risk of
systemic reactions of approximately 10%, but when reactions do
occur to stings after VIT, they are typically mild. Patients who
TABLE I. Possible mechanisms of immunotherapy
Reduction in specific IgE levels (long-term)
Induction of IgG (blocking) antibodies
Reduced recruitment of effector cells
Altered T-cell cytokine balance (shift to TH1 from TH2)
Induction of regulatory T cells
J ALLERGY CLIN IMMUNOL
VOLUME 125, NUMBER 2
receive VIT should be supplied with antiallergic medication for
use in the event of a sting during or after therapy. Some allergists
recommend providing injectable epinephrine during therapy, but
this is not generally considered necessary once the patient has
reached the maintenance dose of SIT.
SIT for allergic rhinitis
SIT is a useful treatment for allergic rhinitis, especially when
the range of allergens responsible is narrow. As with all forms of
SIT, it is important to select patients appropriately. The allergic
basis of the rhinitis should be carefully assessed based on both
history and skin or blood test results, and other causes of nasal
symptoms should be excluded. Direct challenge tests to assess
nasal sensitivity to allergen are not used in routine clinical
practice butmight be useful for assessing effectiveness in clinical
trials. The most difficult group to assess are patients with
persistent nonseasonal rhinitis, especially those who have small
positive skin test responses to house dust mite or other perennial
allergens. In this group it can be extremely difficult to determine
they have nonallergic rhinitis and just happen to be sensitized to
an allergen that is not clinically relevant. This difficulty in
determining clinical relevance contributes to the reported lower
degree of efficacy in SIT trials with perennial allergens compared
with SIT for seasonal allergies.
allergic rhinitis has been confirmed in many trials with grass,
ragweed, and birch pollen extracts.14Importantly, SIT has been
caused by grass pollen that is resistant to conventional drug ther-
apy.15Importantly, this study showed that patients with multiple
allergic sensitizations responded at least as well as those who
were monosensitized to grass pollen.
The benefits of 1 year’s treatment wear off quickly,16but there
are good data showing that 3 years’ therapy provides lasting ben-
efit.17Less well-controlled data show that the effects of SIT can
persist for many years after discontinuing therapy.18This contrasts
with conventional drugs, the effects of which wear off very soon
after discontinuing therapy. The benefits of SIT for perennial rhi-
nitis are less than those for seasonal rhinitis. In part, this reflects
the difficulty in determining the extent to which allergy is respon-
sible for perennial symptoms. Sensitization to house dust mite is
common and does not always cause symptoms. Conversely, there
are other causes of perennial rhinitis, including vasomotor insta-
bility, infection, and aspirin sensitivity. Nevertheless, clinical trials
have shown a definite benefit in appropriately selected subjects.
Clearer evidence has been obtained in patients with rhinitis caused
by pet allergy. Several studies have shown a marked improvement
in tolerance of cat exposure after SIT, which was confirmed both
on challenge tests and simulated natural exposure.19
As with any therapy, the risks and cost-effectiveness of SIT
need to be assessed on a case-by-case basis. Current drug therapy
for rhinitis can be very effective, but a significant minority of
patients have suboptimal control of their symptoms.20Some pa-
tients with rhinitisexperience nosebleeds from intranasal steroids
or excessive drowsiness from their antihistamines; others find
pharmacotherapy inconvenient or ineffective. Moreover, we are
now more aware of the adverse effects of rhinitis on quality of
life. SIToffers a useful option for these patients, as well as a log-
ical approach to dealing with the underlying problem.
SIT for asthma
Immunotherapy has been widely used to treat allergic asthma,
although the introduction of effective inhaled therapies has
changedthegeneral pattern ofasthma care.Concern over adverse
reactions, including a small number of fatalities, has led some
countries (eg, the United Kingdom) to restrict the use of SIT for
asthma treatment, although asthma remains a common indication
for SIT in many parts of North America and continental
Current drug therapies for asthma aim to suppress airways
inflammation and relieve bronchospasm. None of these treat-
ments are curative, and asthma recurs rapidly on ceasing treat-
ment. Allergen avoidance helps in some patients with allergic
asthma, but although extreme forms of allergen avoidance (eg,
admission to the hospital and sending children to holiday homes
at altitude) can improve asthma control, there is only limited
be achieved in suburban homes. There is thus the scope for
improving asthma care and for identifying allergen-specific
therapies. SIT offers the possibility of deviating the immune
response away from the allergic pattern and toward a more
protective or less damaging response. However, SIT remains
controversial as a treatment for asthma because of the potential
The efficacy of SIT in adult asthma has been assessed in many
trialsoverthelast65years.The resultsofthesestudieshave often
been difficult to interpret, either because poor-quality allergen
extracts were used or because of poor study design. Many trials
and in most cases, only small numbers of patients were treated. A
recently updated meta-analysis22identified 75 articles published
between 1954 and 2001. Thirty-six of thesewere for mite allergy,
20 for pollen allergy, 10 for animal dander allergy, 2 for mold al-
lergy, and 1 for latex allergy, and 6 used combinations of aller-
gens. Concealment of allocation was clearly adequate in only
15 trials. A wide variety of different measurements were made,
which makes it difficult to comment on the overall effectiveness
of SIT. Symptom scores improved in the treated groups; it was
tomexacerbation and to treat 5patients to prevent 1 fromneeding
an increase in medication use. SIT reduced the airways response
to inhalation of specific allergen and also improved nonspecific
SIT has a beneficial effect in patients with grass pollen–induced
asthma, as assessed by a reduction in asthma symptom and
treatment scores. Active treatment led to a 60% to 75% reduction
in symptom scores compared with those seen in placebo-treated
patients who received active injections had an improvement in
peak flow rates during the pollen season, as well as reduced hay
fever symptoms and reduced sensitivity to laboratory challenge
with ragweed pollen extracts.23In addition, the active group re-
quired much less antiasthma medication. However, the parallel
economic analysis indicated that the cost savings in asthma drugs
was less than the costs of SIT.
In asthmatic patients sensitive to cats, SIT reduces both the
early asthmatic response to inhaled allergen and responses to
simulated natural exposure in a ‘‘cat room.’’ Interestingly, there
was no protection against allergen-induced increases in
J ALLERGY CLIN IMMUNOL
nonspecific bronchial hyperresponsiveness, despite the clear
delay in onsetof symptoms and an overall reduction in symptoms
and peak flow recordings after exposure to cats. Others have
found reductions in both specific and nonspecific bronchial
reactivity after SIT for cat allergy (measured by using inhalation
challenges with cat extract and histamine, respectively).24
The main drawback in using SIT to treat asthma is the risk of
serious adverse reactions. The vast majority of fatal reactions to
not an absolute contraindication, it is clear that patients with
unstable asthma should not be offered SIT, and caution should be
exercised in anyone with an increased level of asthma symptoms
or transiently reduced peak flow rates.
Comparison of SIT with other types of treatment for
The majority of clinical trials of SIT for patients with asthma
have compared SIT either with untreated historical control
subjects or with a matched placebo-treated group. To date, the
effectiveness of SIT in patients with asthma has rarely been
compared with conventional management (avoidance measures
and inhaled or oral antiasthma drugs). One recent study assessed
SIT in asthmatic children receiving conventional drug therapy
and found no additional benefit in patients who were already
receiving optimal drug therapy.25There were some significant
flaws in the design of this study, and further work of this type is
Effects on natural history of allergic disease
Children often start with a limited range of allergic sensitivities
allergens. Treatment with SIT might limit this tendency to acquire
effect is not clear. A proportion of patients with allergic rhinitis
develop asthma each year. This annual rate of progression has
been estimated at 5% in college students,27but this is perhaps sur-
prisingly an area of considerable ignorance. A number of long-
term epidemiologic studies are now in progress under the auspices
of the International Study of Asthma and Allergies in Childhood,
and these should eventually shed light on the rate of progression
at different ages and the extent of regional and international varia-
tion. It has been suggested that SIT might modify the natural his-
toryofasthmainchildrenwho are knowntobeatopic buthave not
yet developed asthma. Only limited data are available to support
this proposition. In the key study a group of 205 children aged 6
to 14 years without previously diagnosed asthma were treated
with SIT for birch or grass pollen allergy in an open randomized
design. Three years after completing treatment, 45% of the un-
treated group had asthma, whereas only 26% of the treated group
had asthma. These results have been sustained out to 7 years after
completing therapy. Thus 4 children had to be treated to prevent
1 case of asthma, which makes this an extremely effective ther-
apy.28SIT might also modify the progression of established
asthma. An early open study with uncharacterized mixed allergen
extracts supported this view, with about 70% of treated children
losing their asthma after 4 years’ therapy compared with about
19% of untreated control subjects, a result that was sustained up
to the age of 16 years. The proportion of children whose asthma
was severe at age 16 years was also much lower in the treated
group.29By modern standards, this study was not well designed,
and it needs repeating with modern SIT extracts in an up-to-date
In contrast, there is no current evidence that SITinfluences the
evolution of established asthma in adults. Studies that have
asthma symptoms, although rhinitis symptoms seem to show
much more sustained relief after SIT.30
Thus SIT is a valid but controversial treatment for asthma.
Although it seems entirely logical to try to treat allergic disorders
by specifically suppressing the immune response to the triggering
agents, the critical issue is whether SIT in its present form is the
best option for managing patients with asthma. To assess this
properly would require comparisons of best current SIT versus
best current drug therapy, with robust end points including
symptoms, objective measures of lung function, evaluation of
cost/benefit ratios, safety, and quality of life. In vitro and in vivo
measures, such as skin test responses or allergen-specific IgG4
measurements, are not sufficiently specific or sensitive to serve
as surrogates for clinical efficacy. To date, there have been rela-
tively few well-controlled studies of SIT in asthmatic subjects,
but there is increasing evidence that SIT is beneficial in patients
with mite-induced and pollen-induced asthma. The clinical effi-
cacy of SIT in adult asthmatic patients sensitive to cats or molds
is less certain, and no comparative studies with conventional
treatment have been performed. Further clinical trials are indi-
cated, particularly in patients with mild-to-moderate childhood
asthma and also in patients with atopic disease who have not
yet had asthma but are at high risk of progression to asthma.
Safety of SIT
The most obvious risk of SIT is that of provoking a systemic
allergic reaction.In the UnitedKingdombetween 1957 and 1986,
26 fatal reactions caused by SITwere reported to the Committee
to treat their asthma. Similarly, in the American Academy of Al-
lergy, Asthma & Immunology inquiry into SIT-associated deaths,
asthma appeared to be the cause of death in most of the fatal
cases.32,33In those cases in which asthma was not cited as a con-
chospasm was a feature of the clinical course of the fatal
as an end point is that we have to accept that all treatments carry
risks. Where differential risks exist between therapies, a more
additional benefit over the safer therapy. The science of assessing
risk/benefit ratios is still in its infancy, and we have to recognize
that even when faced with the same facts, different patients and
agencies can come to widely varying risk assessments. However,
where possible, we should take steps to minimize the risks.
Separately, there is some concern about the use of immuno-
modulatory treatments in patients with autoimmune disorders,
immunodeficiency syndromes, or malignant disease. Although
there is no hard evidence that SIT is actually harmful to these
patients, some clinicians feel uncomfortable about manipulating
the immune system in such patients, not least because of the risk
that spontaneous and unrelated variations in the autoimmune
J ALLERGY CLIN IMMUNOL
VOLUME 125, NUMBER 2
disorder or cancer might be blamed on SIT. However, provided
the risks and benefits are weighed and discussed with the patient,
SIT can be administered where the risk/benefit ratio is considered
include the coexistence of significant cardiac disease that might
be exacerbated by any adverse reactions to SIT. b-Blockers are
also contraindicated in patients receiving SIT. Although they do
not increase the risk of adverse reactions, they will prevent the
patient from responding to the epinephrine that might be needed
to treat adverse reactions to SIT. Where the indication for SIT is
strong, alternatives to b-blockers should be used so that the SIT
can be given safely. Some clinics advise avoiding angiotensin-
converting enzyme inhibitors because they can accentuate angi-
oedema (angiotensin receptor antagonists [sartans] do not share
Alternative forms of immunotherapy
Alternative allergy practice covers 3 principal themes: the use
of unconventional diagnostic tests to seek causative agents for
diseases that everyone agrees are allergic in origin; the use of
unconventional therapies to treat allergic disease; and the diag-
nosis and therapy of diseases that are not conventionally consid-
ered to involve allergic mechanisms. Alternative immunotherapy
regimens fall into the second of these categories, but the other 2
areas fall outside the scope of this review.
Unconventional forms of immunotherapy include the use of
and homeopathic desensitization.
Topical immunotherapy. High-dose topical immunother-
apy regimens were used in the first half of the 20th century but
subsequently fell into disrepute. The last 20 years have seen a
revival of interest in sublingual immunotherapy (SLIT). The
precise mechanisms by which sublingual SIT works remain
unclear. In mice locally administered allergen is taken up by
IL-12, biasing the response toward a TH1 profile and away from
the pro-IgE TH2 profile. It is less clear whether this mechanism
can suppress established allergic responses. In contrast, the im-
munologic response to SLITin human studies has been relatively
modest. Some changes have been found in skin sensitivity, but
most studies have not found any change in systemic parameters,
such as specific IgE, specific IgG, or T-cell cytokine balance.
A body of evidence has accumulated from well-conducted
clinical trials indicating that SLIT can be effective, with up to
30% to40%reductions insymptom scoresand rescue medication
use in patients with seasonal allergic rhinitis.34Treatment regi-
mens typically involve a rapid build-up phase followed by treat-
ment given either daily or 3 times per week with rapidly
are supplied in liquid form, with a calibrated dropper. A recent
meta-analysis of SLIT found 22 studies in which 979 patients re-
ceived active therapy.34Although many of these studies were
small and inconclusive, the combined results indicate that SLIT
is indeed effective, with an estimated power of about two thirds
that seen in comparable studies ofinjected SIT. Local side effects
were common but well tolerated.
In the grass pollen tablet trials about half the patients experi-
encedsomelocalirritation withthefirstdose. Thiswasminorand
generally did not require a reduction in subsequent doses. About
half of those with initial side effects had lost these by the eighth
day of treatment; only 1 in 25 of all patients had continuing local
relatively rare, and none of the side effects were judged to be life-
threatening. For perennial allergens, less trials data are avail-
able,36and only limited data are available in children, although
the most recent studies have been encouraging.37,38Other forms
of topical immunotherapy (oral and nasal) have limited efficacy
but are associated with high levels of side effects.
SLIT is now being used routinely in some parts of Europe
(especially Italy and France), but often the doses and regimens
As performed in the published trials, SLIT involves giving 20 to
SIT. There is no evidence that giving smaller doses sublingually
SIT and bring in additional prescribers. As with all forms of
immunotherapy, patient selection will be the key to ensuring that
therapy is targeted to those who are likely to benefit from it.
Some areas of uncertainty remain. For example, the optimum
duration and durability of therapy have not been defined. Recent
clinical trials have confirmed that the benefits of SLIT persist for
the first year after discontinuing treatment, but if they do persist,
for how long do they persist? Based on experience with injected
3 years, although most clinical trials were short-term (6-12
months). For seasonal allergens, most open-label use in clinical
practice has been intermittent, starting 2 to 3 months before the
season and stopping at the end of the season. However, the
manufacturer of the only licensed product recommends starting 4
months before the first grass pollen season and continuing
throughout the year for 3 years. This has major implications for
direct costs and cost-effectiveness,39and some supporting data
would be welcome.
The relative efficacy of SLIT and injected SIT has not been
determined. The only published comparative studies were far too
small to produce meaningful results.40,41Based on the effect size
seen in the meta-analyses,14,34it seems likely that SLIT has be-
tween 60% and 100% of the efficacy of injected SIT, although
it is difficult to make a true comparison.
EPD. In EPD very small doses of allergens are given together
with the enzyme b-glucuronidase. The allergen doses are ap-
proximately 0.1% of the doses used in conventional SIT, and side
effects are apparently not encountered. The theory behind EPD is
that the b-glucuronidase enables the allergen to gain access to the
immune system more efficiently than is possible with conven-
tional SIT. No convincing evidence has been published to support
the efficacy of EPD.
Homeopathic desensitization. A detailed discussion of
the principles underlying homeopathy lies outside the scope of
this chapter. However, homeopathy espouses the concept that
diseases can be treated with very small doses of substances that
the disorder. Thus homeopathic remedies for hay feverbear some
superficial similarity to SIT. A systematic review of homeopathy
has concluded that homeopathy did appear to offer some benefit
in patients with hay fever and cited trials of homeopathy in hay
fever as an example of good practice in homeopathic research.42
However, a more recent, carefully controlled study of homoeopa-
patients with asthma.43
J ALLERGY CLIN IMMUNOL
There is scope to improve conventional SIT (Table II). Possi-
ble avenues include the use of recombinant allergens, which
would improve standardization of allergen vaccines and might
allow fine tuning of vaccines for patients with unusual patterns
of reactivity. Most allergic patients react to the same components
of an allergen extract, the so-called major allergens, which are
defined as those allergens recognized by more than 50% of
sera from a pool of patients with clinically significant allergy
to the material in question. However, not all patients recognize
all major allergens, and some patients only recognize allergens
that are not recognized by the majority of allergic patient sera.
This latter group might not respond to standard extracts but
might be better treated with a combination of allergens to which
they are sensitive. Now that recombinant allergens for SIT are
available, the range of sensitivities can be better characterized,
and this might lead to patient-tailored vaccine products. Thus
far, clinical trials have confirmed the efficacy of recombinant
allergen cocktails but have not yet shown superiority to conven-
major birch pollen allergen Bet v 1 has been made. This trimer is
much less allergenic, even though it contains the same B-cell and
T-cell epitopes as the native molecule and induces TH1 cytokine
release and IgG antibodies analogous to the antibody response
to standard SIT.45Folding variants and other modifications of
the physical structure might also improve the safety of SIT.46
Because the epitopes recognized by IgE molecules are usually
3-dimensional, whereas T-cell epitopes are short linear peptide
fragments of the antigen, it should be possible to use peptide
fragments of allergens to modulate T cells without risking
anaphylaxis. Two distinct approaches have been tested. Either
large doses of natural sequence peptides are given, deceiving the
T cell into high-dose tolerance,47or else an altered peptide ligand
can be given. Both approaches require consideration of the MHC
type of the subject undergoing treatment. By means of sequential
alteration of Dermatophagoides pteronyssinus peptides, it is pos-
sible to suppress proliferation of T-cell clones recognizing native
D pteronyssinus peptides, as well as suppressing their expression
of CD40 ligand and their production of IL-4, IL-5, and IFN-g.
These anergic T cells do not provide help for B cells in class
switching to IgE, and importantly, this anergy cannot be reversed
by providing exogenous IL-4.48
In an animal model intranasal application of genetically
produced hypoallergenic fragments of Bet v 1 produced mucosal
tolerance, with significant reduction of IgE and IgG1 antibody
responses, as well as reduced cytokine production in vitro (IL-5,
IFN-g, and IL-10). These reduced immunologic responses were
that were seen with the complete Bet v 1 allergen. The
mechanisms of immunosuppression seemed to be different for
the allergen fragments and the whole molecule in that tolerance
induced with the whole Bet v 1 molecule was transferable with
spleen cells, whereas that induced by the fragments was not.49
From epidemiologic and experimental studies, we know that
vaccination with mycobacteria has antiallergic properties. In
Japan early vaccination with BCG was associated with a sub-
stantial reduction in the risk of allergy,50although similar associ-
ations were not evident in Sweden.51In an animal model it has
been shown that administration of BCG before or during sensiti-
zation to ovalbumin reduces the degree of airway eosinophilia
that follows subsequent challenge with ovalbumin. This effect
is not mediated through any direct effect on IgE production or
blood eosinophil numbers but is mediated through IFN-g and
can be reversed by exogenous IL-5.52
Two new approaches using DNAvaccines are also undergoing
CpG oligodeoxynucleotides that mimic bacterial DNA and stim-
ulate TH1-type cytokine responses. In a murine model of asthma,
preadministration of CpG oligodeoxynucleotides prevented both
airways eosinophilia and bronchial hyperresponsiveness.53More-
enhances immunogenicity in terms of eliciting a TH1-type re-
TH1 cytokine expressioninculturedhumanPBMCs.56Initialclin-
sponse,57but subsequent trials have been inconclusive. A
contrasting approach is to use allergen-specific naked DNA se-
liminary data suggest that administering naked DNA leads to
production of allergens from within the airways epithelial
cells.58,59Because of the different handling pathways for endoge-
duced allergen elicits a TH1-type response, and if this can be
reproduced in allergic human subjects, it is hoped that this might
overcome the existing TH2-pattern response and eliminate the al-
lergy. However, the potential for generating a powerful TH1-type
SIT has been used for more than a century and is clinically
effective in patients with rhinitis or asthma whose symptoms are
clearly driven by allergic triggers. Perhaps surprisingly, we are
still unsure exactly how SIT works, but we do know that SIT
induces regulatory T cells that dampen the response to allergen
exposure in sensitized subjects. When used in appropriately
selected patients, SIT is effective and safe, but care is needed to
recognize and treat adverse reactions. As well as careful patient
selection, appropriate training of allergists and SIT clinic support
staff is essential. Future directions in SIT will include the
development of better standardized vaccines and the use of
recombinant allergens, both of which should improve the safety
profile of SIT. In parallel, the development of allergen-indepen-
dent immunomodulatory therapies might allow more general
approaches to be developed, which would be particularly advan-
TABLE II. Possible new technologies for immunotherapy
Hypoallergenic allergens (bioengineered recombinant molecules)
T-cell peptide vaccines
TH1 immunostimulants (eg, mycobacteria and CpG)
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