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Can Immunotherapy Cure
Allergies?
Project Aims:
• To demonstrate an understanding of the basic pathophysiology
of allergy.
• To demonstrate an understanding of the main mechanisms of
tolerance
and
their
application
in
allergenimmunotherapy.
• To discuss the literature surrounding specific immunotherapy
(SIT), peptide-based immunotherapy (PIT) and the main
methods of delivery.
• To review the current evidence for the treatment of a) allergic
rhinitis and b) peanut allergy, including the barriers and
risks in the treatment of these.
This site was made by a group of University of Edinburgh
medical students who studied this subject over 10 weeks as part
of the SSC. This website has not been peer reviewed. We certify
that this website is our own work and that we have authorisation
to use all the content (e.g. figures / images) used in this website.
We would like to thank Dr Mackenzie for her guidance
throughout this project.
Total Website Word count: 9,538
Word count minus Contributions Page, References Page,
Critical Appraisal Appendix, Information Search Report, Word
Version
Appendix and other sections clearly marked as
Appendices: 5,952
Introduction
Allergy as a concept was first introduced in 1906 by the
Viennese paediatrician Clemens von Pirquet after he noted that
some of his patients were hypersensitive to normally innocuous
entities such as dust, pollen or certain foods. This
understanding was further enhanced in the 1960’s with the
breakthrough discovery of the antibody IgE[1]. Today, we have
a developed knowledge of allergies and are researching more
than ever.
However, allergy is an ever-expanding problem in the Western
world - prevalence in the UK is thought to have trebled in the
past three decades alone and is currently estimated to
affect around one third of the UK population in one form or
another, including asthma, eczema, allergic rhinitis and food
allergy[2]. It is common for children with one allergic disease to
develop further allergic disease during childhood - a theory
known as the "allergic march"[3].
The popular “hygiene hypothesis” states that lack of early
childhood exposure to infectious agents, parasites and symbiotic
microorganisms has increased susceptibility to allergy by
dampening the immune system’s natural development and
evolution[4]. Another theory is that lack of exposure to an
allergen in the early years can increase the likelihood of
developing such an allergy later in life. One study found that
Israeli children who are exposed to peanuts early on - through
the popular peanut snack, 'Bamba' - were 10 times less likely
to develop a peanut allergy than those in the UK where early
avoidance is recommended[5].
As aforementioned, research is ongoing for allergy management
and treatment - immunotherapy being at the forefront. With a
vast range of administration routes currently being researched,
the question of specific versus peptide immunotherapy and the
mysteries of dosage and efficacy yet to be fully answered,
immunotherapy is a promising potential treatment which will
require more investigation for a fully evidenced treatment to
emerge[6].
Aims
Pathophysiology of Allergy
Allergies are type 1 hypersensitivity disorders that trigger
immune responses to allergens that would normally be
registered as harmless. This hereditary predisposition to
harmless antigens resulting in inappropriate IgE production
and the consequent immune response is called atopy[7].
The first time an allergy-prone person encounters an allergen the
exposure should only produce a mild reaction, but repeated
exposures may lead to more serious reactions due to the
mechanism of sensitisation[7]. The initial antigen is presented
to naïve T cells by antigen-presenting cells (APCs), causing
them to develop into TH2 cells and undergo clonal expansion.
This leads to the production of cytokines: specifically IL-4
which acts in a positive feedback loop to promote differentiation
of naïve helper T cells to TH2 cells as well as triggering
increased IgE production, firstly by class switching and then by
clonal expansion of B cell populations[8]. These IgE antibodies
circulate in the blood and bind to specific FcεR receptors on
mast cells and basophils, making them sensitised to the allergen.
IgE has a short half-life of only 2-3 days[9] when in the blood,
but when bound to mast cells and basophils this extends to 3
months. This is what causes the predisposition within sensitised
individuals, which can occur due to several factors. Genetic
factors result in T cells producing the ‘wrong’ cytokines; IL-4
and IL-13 production is favoured to induce class switching in B
cells to IgE production. Environmental factors involve
the hygiene hypothesis[10] where individuals are exposed to
fewer microorganisms by being brought up in environments
which are ‘too clean’, leading to class switching to IgE as less
of the other isotopes are required.
Immediate phase reaction (type 1 hypersensitivity)
Allergen crosslinking of FcεR-bound IgE leads to
degranulation and release of vasoactive amines (histamines,
prostaglandin D and platelet-activating factor) causing an
immunological reaction creating allergic symptoms. These
include vasodilation, increased vascular permeability, mucus
production and bronchoconstriction. In severe cases
anaphylactic shock can ensue which is a system-wide reaction
affecting skin as well as respiratory and cardiovascular systems,
often resulting in death if not treated quickly[11]. Localised
allergic reactions such as asthma or eczema remain within
certain regions of the body dependent on exposure of allergen.
Late phase reaction (allergic inflammation)
Following migration to sites of allergen-exposure by
chemotactic factors, antigen-specific T cells are reactivated and
clonally expand. Local IgE-facilitated antigen presentation by
dendritic cells increases T cell activation[12]. This results in
allergic rhinitis and asthma characterised by increased mucus
production and bronchial epithelial cell apoptosis. Atopic
dermatitis also results in keratinocyte apoptosis[8].
Mechanisms of tolerance
Tolerance is the natural phenomenon which prevents
our body's immune system from reacting to innocuous or selfsubstances. It plays a critical role in our everyday lives
where life-threatening allergic reactions can be a potential
consequence. Immunotherapy aims to diminish this immune
response by initiating tolerance: training the body to recognise
and ignore these allergens.
Tolerance
Clonal deletion:
Several mechanisms of tolerance in the human body have been
recognised. In the thymus, T cells are positively selected for
their ability to recognise 'self' antigens[13], and are then
negatively selected if this results in strong binding. This is
termed clonal deletion. It is also during positive selection that T
cells are further divided into CD8+ and CD4+ T cells,
depending on whether they recognise MHC class I or II
molecules respectively. Those which recognise neither undergo
apoptosis, ensuring that T cells with high affinity and those with
no affinity for MHC are eliminated[14] before becoming
immunocompetent[15].
Anergy:
This is a state where T and B cells are temporarily static and
unable to be activated[15]. Anergy can occur in T cells at their
initial meeting with antigens, prior to dendritic cells being in
attendance. Similarly, in B cells anergy can occur prior to the
arrival of T cells to costimulate them[15]. The cells require
multiple signals before they can mount an immune response and
this is crucial in eradicating self-reactive immune cells which
have managed to mature and migrate to the peripheries.
Regulation:
In contrast to the previous mechanisms, regulation has only
recently begun to be understood. In 1970, work by Gershon and
Kondo first suggested the existence of T cells other than helper
T cells with the ability to tone down the immune response: so
called 'suppressor' T cells[16]. Their proposition was met with
controversy and largely brushed aside as established evidence
already existed for populations of T cells secreting various
cytokines which modulated the immune response, such as the
IL-10-secreting Tr1 cells, and without much other evidence this
was widely accepted as their main suppressive mechanism[17].
It was not until the mid-1990s that studies utilising cell surface
marker CD25+ led to the identification of CD4+CD25+ T
cells[18]. Demonstration by Sakaguchi and colleagues that
removal of this cell population triggers autoimmune disease –
and furthermore enhances immune response to non-self antigens
– supported their specific role in tolerance[18]. The resulting
population were named regulatory T cells, or natural Treg cells
(nTreg) due to their continuous natural production in the thymus.
Breakthrough research in 2001 led to discovery of the Foxp3
gene, the mutation of which causes IPEX in humans (immune
dysregulation, polyendocrinopathy, enteropathy, X-linked
syndrome), resulting in autoimmune disease and severe
allergy[19]. Further study in mice showed Foxp3 expression was
primarily limited to the CD25+CD4+ T cell population and, in
addition, retroviral transduction of Foxp3 to naive T cells
resulted in their conversion to cells resembling Treg cells
and with a similar suppressive function[20]. This research
suggested the exciting potential for induction of Treg population
of cells to treat immune disease.
Allergen Immunotherapy
Allergen immunotherapy aims to utilise the mechanism of
regulation and the powerful influence of T cell populations to
alter the allergic disease process. Allergen-specific effector T
cells skewed towards a regulatory phenotype appear to relate
to successful outcomes of immunotherapy[21].
The major Treg cells immunotherapy aims to induce are
nTreg cells and IL-10-secreting Tr1 cells[22]. A combination of
actions by Treg cells are thought to contribute to the induction of
tolerance; the suppression of TH2 cells leads to reduction
in several of its actions, such as IgE production and mucus
production by the epithelium. IL-10 and TGF-β directly and
indirectly regulate B cells and effector cells[23].
Meanwhile, B cell activity is modified with a class switch from
IgE to another non-allergy promoting antibody isotype: IgG4.
This antibody diminishes the immune response by competing
with Fcε receptors on IgE for binding antigen, limiting IgEactivated mast cell and basophil degranulation[24]. IL-10producing B cells and memory B cells have been shown to
contribute to expression of IgG4, which is found to be elevated
in those demonstrating maintained peripheral tolerance[25].
Beekeepers demonstrate the phenomenon of natural tolerance;
during particular seasons they are exposed to more bee venom,
and yet demonstrate immunity other than local effects at the site
of the sting[26]. It is suggested that this is due to an increase
in IgG4 levels[26]. Outwith these seasons of increased exposure,
however, IgG4 levels decrease, which could be explained by the
irregular frequency of exposure preventing long-term tolerance
from being achieved[26].
A trial by Caubet et al in egg-allergic children showed a
decreased IgE/IgG4 ratio in tolerant children compared to those
who experienced reactions to baked egg; the increase in IgG4
levels was only detected after a steady, prolonged period of
antigen exposure[27]. Other clinical research supports the vital
role of these 'blocking' antibodies: in patients whose
immunotherapy was discontinued, IgE levels returned to
previous parameters but clinical tolerance alongside
increased IgG4 was maintained for up to two years[24].
Previously, difficulties in demonstrating the link between
blocking antibodies and increased immune tolerance to allergens
was due to lack of correlation between antibody levels after
tolerance has been achieved, as these are noted to decrease[24].
This has led to the consideration of an altered activity and
affinity of specific IgG subsets, rather than serum levels, that is
ultimately responsible for the long-term effects of
immunotherapy[24].
Advances in immunological research have uncovered the role of
vital cell types in the immune response. Mechanisms of clonal
deletion and anergy are relatively well understood whilst,
despite decades of research, the regulatory effect of T cells still
requires in-depth research. The classification of Treg cells
remains controversial as their suppressive activities are not
exclusive and have been exerted by conventional TH cell
subtypes in some experiments[28]. It is hoped that with
continued intensive research geared towards a
fuller understanding of the induction of T cell regulation, the
field of immunotherapy can further progress towards improving
the design and success of the clinical treatment.
Clinical aspects of immunotherapy
Allergen-Specific Immunotherapy
Allergen-specific immunotherapy (allergen-SIT) involves
administration of allergen proteins to patients in increasing,
tolerable doses to build up peripheral tolerance and modulate
the immune response. It is currently regarded as the single
curative approach to allergic disease[29]. The induction of
peripheral T cell tolerance and promotion of Treg cell formation
are key mechanisms in SIT[29]; this approach has shown success
in the clinical treatment of allergic rhinitis (AR) and asthma
with many studies conducted over the last 80 years establishing
its effectiveness[30][31].
A major difficulty with SIT is the frequency of local and
systemic adverse events, particularly during the early stages
where serum IgE levels modestly increase as seen in the graph
above[32]. These adverse reactions range from mild to lifethreatening anaphylaxis, rendering SIT an effective therapy
fraught with risk[33]. Though this has been overcome in some
studies by using ultra-rush procedures[29], it remains
problematic: whilst high doses of SIT are associated with a
higher risk of these adverse events, low doses are found to be
ineffective[30]. It is therefore critical to calculate an optimal
dosing plan to strike the correct balance between the two.
An effective dosing plan must ensure several factors: the
induction of therapeutic tolerance, achievement of long-term
change in T cell populations and absence of serious adverse
effects.
When
explored
within
the
autoimmune
encephalomyelitis model of multiple sclerosis in mice, treatment
with subcutaneous self-peptide immunotherapy demonstrated
the strong dose-dependent nature of tolerance induction
using several markers (e.g. IL-10 levels and severity of
disease[34]). The study also indicated that high initial antigen
doses induced adverse effects across almost all of the mice.
Dose escalation was therefore found to be vital, with the ability
to diminish adverse effects and lower or delay the level of
inflammatory cytokines.
Many studies also indicate that the frequency of dose
administration is essential. In immunotherapy treatment of
mouse models sensitised to a grass allergen, lower allergen
doses administered daily were found to have greater efficacy
than higher allergen doses administered less frequently – despite
identical weekly cumulative doses – suggesting that daily doses
are preferential[35].
A number of recent studies have confirmed the long-term
clinical effects of SIT years after cessation of treatment. In one
study for preventative treatment of childhood asthma,
participants were successfully treated for 3 years with pollenSIT and followed up 2 and 7 years after cessation of treatment,
demonstrating persistence of the original immunotherapeutic
benefits[36][37]. However, more evidence is needed to establish
how long particular therapies must be administered for to ensure
long-term maintenance of tolerance.
Peptide Immunotherapy
Peptide immunotherapy (PIT) involves the use of short
synthetic peptides which represent dominant T cell epitopes of
the allergen. These have a reduced ability to crosslink IgE and
activate mast cells and basophils (mostly due to lack of tertiary
structure[33]) whilst still inducing a response in CD4+ T
cells[21].. This simply initiates a T cell-dependent late stage
reaction, thus reducing the health risks to patients[38]. PIT has
shown some beneficial results in early stage trials for the
treatment of both insect venom and cat allergies, although
research in these areas is ongoing[21][39].
In 2002, Larche et al trialled PIT for the treatment of cat allergy
and found that patients receiving Fel-d 1 (major cat allergen)
peptides reported a significant improvement in their tolerance to
cats at second follow-up, with only mild adverse reactions
during treatment. Bias is reduced due to the study's doubleblinded nature, therefore this was a promising result[40].
Various trials have been undertaken since, including one in 2011
by Patel et al which investigated long-term tolerance. 89 patients
were enrolled in a 1-year blinded follow-up to PIT which
showed
improvement
in
symptoms
compared to
placebo[41].The importance of dosing on efficacy was also
highlighted as there were significant differences in long-term
tolerance between patients who underwent different dosing
regimens[41]. However, due to the variability of these
results more research would be required to prove efficacy[42]. In
contrast to SIT, there have been no severe or anaphylactic
adverse reactions in participants treated with PIT, therefore this
could be hugely beneficial for treatment of children [42]. There
has been some research into the characterisation of T cell
epitopes for peanut allergen but no clinical trials have yet been
undertaken[43].
Methods of administration
Currently the evidence base for SIT is extensive, thus varying
methods of administration centre around this form of
immunotherapy.
Subcutaneous immunotherapy
Subcutaneous immunotherapy (SCIT) generally involves
weekly allergen injections during a build-up phase, followed
by monthly maintenance injections for 3–5 years[44] .
SCIT is highly effective in seasonal AR. A narrative review of
43 DBPC trials confirmed efficacy (greater than 30% when
compared to placebo in 75-80% of studies[45]). In general,
clinical efficacy is accompanied by a marked reduction in
requirements for anti-allergic medication during the pollen
season and a marked improvement in patients' quality of
life[46]. Additionally, a Cochrane meta-analysis of 62
randomised controlled trials performed between 1954-1998
demonstrated significant improvements in allergic asthma
symptoms, reduction in rescue medication and improvements in
both allergen-specific and non-specific bronchial hyperresponsiveness[31].
Unfortunately SCIT is time-consuming and requires medical
supervision for the administration and immediate period
following injection due to risk of severe systemic allergic
reactions[47]. In one particular report, for instance, 16/17
fatalities were in SCIT patients with co-existing poorly
controlled asthma[48]. For this reason, severe forms of allergic
disease are not treated subcutaneously, e.g. peanut allergy[48].
Sublingual immunotherapy
Sublingual immunotherapy (SLIT) involves placing an allergen
extract under the tongue for a few minutes. It is more patientfriendly due to the lack of injections so can performed at home;
it additionally results in less severe reactions than SCIT. A
2011 publication tracking individual prescriptions for SCIT and
SLIT in a national German database found that persistency rates
for SLIT (51%) were significantly higher after two years than
those for SCIT (34%)[49]. However, SLIT is still timeconsuming and needs to be administered daily for several
years[49].
There are many papers arguing that SLIT may be less effective
than SCIT. Chelladurai Y et al directly compared existing
clinical trials to assess differences in efficacy and safety
between SCIT and SLIT with regards to AR[50]. Focusing purely
on the relief of AR symptoms, the results found that in 5 out of
6 trials, SCIT relieved symptoms more effectively than SLIT.
Having said that, the last trial reported no significant difference
between the two methods but this still leaves some evidence to
support SCIT’s superiority[50]. However, this review recognises
that more direct comparison trials would be required to
strengthen the evidence base[50].
A further 2014 indirect comparison of DBPC trials in Canada
specifically examined the literature around use of SCIT, Oralair
and Grazax (SLIT tablets) and established a cost benefit in
Oralair-prescribing without sacrificing safety or efficacy, a
finding which could prove instrumental if transferable to other
countries[51]. However, it should be noted that the manufacturers
of Oralair funded the trial so bias may have arisen; further
research would have to be undertaken by a third party to
determine the reliability of these conclusions[51].
Oral Immunotherapy
Oral immunotherapy (OIT) involves orally administering food
allergens (whole or cooked) to patients. Early stage trials have
shown promising results for this method in the treatment of
peanut, egg and cow’s milk allergies[52][53][54].
OIT is currently the most promising treatment for peanut
allergy as it stimulates greater immunologic changes in
volunteers, specifically lower peanut-specific IgE and basophil
activation levels and raised IgG4, as well as participants being
able to tolerate greater doses post-immunotherapy[55].
OIT has the benefit of being much more patient friendly than
other types of immunotherapy: it does not require injections and
is easier to administer[56]. However, it is also reported to cause
unpleasant side effects such as diarrhoea and vomiting in some
patients[57].
Other Administration Routes
Nasal administration: Involves an inhaled powder/solution or
coated strips placed within the nasal passages. Potential
therapeutic benefits have been demonstrated in the treatment of
dust mite-mediated allergic rhinitis[58].
Intralymphatic administration: Allergens are injected directly
into the inguinal lymph nodes. One trial demonstrated that 3
intralymphatic injections provided similar benefits to 3 years of
standard SCIT for the treatment of AR and led to less severe
allergic reactions[59]. However, some trials published did not
demonstrate efficacy versus placebo[60].
Epicutaneous immunotherapy (EPIT): A new, non-invasive
delivery route. A DBPC trial of 132 patients with grass polleninduced AR showed significant improvement compared to
placebo[61]. Phase II peanut EPIT trials are currently being
undertaken so its safety, efficacy and potential for use is yet to
be seen[62].
Allergic Rhinitis
Allergic rhinitis (AR) involves the interaction of an allergen
with the nasal airways, evoking an allergic response[63]. It is
very common in western countries, currently affecting over 20%
of people in the UK[48] although recent evidence suggests that
its prevalence is gradually increasing[64]. Although AR carries
little risk in terms of mortality to afflicted individuals, there
remain significant disturbances to daily life as well as
associated comorbidities which may be aggravated[65].
In most cases there is sufficient temporary relief of symptoms
by taking antihistamines, eye drops and/or intranasal
corticosteroids[48], but in severe cases this may not be enough.
AR has therefore been a frequent target for clinical research
into immunotherapy in order to relieve its characteristic coldlike symptoms[63]. As it stands, the two main routes of
administration in the UK are sublingually as Grazax
tablets[66] and by subcutaneous vaccine[67].
A clinical trial conducted in 2010 investigated the ability of
Grazax to induce immunological changes in patients with
AR[66]. This was a multicentre randomised DBPC trial, and
baseline characteristics were measured to ensure that the control
and active groups had similar IgE and IgG4 levels. The raw
results showed a significant increase in IgG4 levels of patients
in the active group, but no substantial change in the placebo
group, suggesting that the results were valid and Grazax does
have a positive immunological effect on the body. However the
study did not mention whether or not Grazax actually relieved
the patients’ symptoms – an important factor in measuring the
efficacy of the drug[66].
Alternatively, some trials have been more focused on patient
satisfaction and relief of symptoms rather than solely
immunological effects. Bergman et al conducted a large
multicentre trial testing the safety and efficacy of SLIT for
house dust mite-induced AR, and demonstrated that a significant
reduction in symptoms could be achieved and maintained for at
least a year following a year of therapy[65].
Patient diaries were used in which participants scored their
symptoms daily to gauge trends and detect self-reported
changes, which was ultimately an effective method for
indicating the improvements in quality of life experienced
from a subjective point of view[65]. This trial also caused
very few side effects as a result of the sublingual route of
administration: every participant who had taken one or more
dose of therapy was included in the results for safety, and of
these 509 randomised participants no anaphylactic events were
recorded at any point during the course of treatment, or in the
subsequent treatment-free year[65]. This was replicated by
Mosbech H et al in a recent trial (study population 608 across 8
European countries) where similar results for both safety and
efficacy of SLIT to combat dust mite-induced AR and asthma
were demonstrated[68].
Both of the aforementioned trials utilised large study
populations, double blinding and randomisation procedures
which reduced the risk of bias during the trials, although it
should be noted that both were sponsored by the pharmaceutical
company whose drug was being trialed and so results may have
been biased in this way. These results were again reinforced by
a trial utilising the intralymphatic delivery route (though on a
much smaller scale) which nonetheless demonstrated a
significant improvement noted by participants in quality of life
upon receiving the active treatment, as well as no severe adverse
events[69]. This data demonstrates the positive influence that
immunotherapy can have on the lives of those suffering from
AR, without causing unnecessary detriments to health.
A 2013 retrospective analysis conducted in Florida investigating
the issue of cost found sufficient evidence of economic benefit
in immunotherapy in these individuals. This concurred with
previous research which has similarly shown a stark advantage
in providing this therapy in children to prevent the allergic
march from progressing, whilst further demonstrating that the
benefit was paralleled when introduced in adulthood[70]. This
study may have encountered bias due to its retrospective nature
so should not be treated as absolute, but it may be a useful
comparison should this issue be investigated in the UK.
Peanut allergy
Peanut allergy is the most common food allergy in adults and
children, estimated to affect 1 in 50 young infants[71] with
evidence to suggest its incidence is constantly
rising[72]. Although children often grow out of other food
allergies such as cow’s milk allergy, only around 20% of
childhood peanut allergies will resolve[73].
Clinical symptoms of the allergic reaction include hives,
vomiting and anaphylaxis, though the form and severity of
symptoms ranges widely between individuals[74]. Currently
treatment is limited to the management of symptoms, meaning
the only option for allergic individuals is to simply avoid
peanuts. Accidental exposure can only be dealt with by prompt
treatment using antihistamines for acute cases or adrenaline in
more severe reactions[75]. In fact, evidence suggests that early
treatment with adrenaline is crucial to prevent death in severe
anaphylaxis[76]. Unfortunately, in a minority of cases the
allergic reaction still leads to fatalities[77]. The significant
prevalence of peanut allergy, as well as its potential to induce
life-threatening anaphylaxis, makes it a great priority for
immunotherapy research.
Currently there is much promising research into peanut
desensitisation through the use of immunotherapy[78].
Originally, the method of administration investigated was
subcutaneous[79]. The first of two SCIT trials was undertaken
in 1992, but was quickly halted after the death of a young boy
due to a mix-up of injections[80][81]. The subsequent trial,
undertaken in 1997, showed too high a rate of systemic
reactions to be considered in clinical practice[79].
Peanut-immunotherapy has only begun to produce truly
convincing results following the success of several groundbreaking OIT trials carried out in 2009[82][83]. Clark et al
found increasing amounts of peanut flour administered to four
male children over several months demonstrated induction of
tolerance[82]. A post-intervention challenge showed an
increased dose threshold in all participants ranging from 49-478
times greater. This demonstrated the great potential of OIT for
peanut allergy sufferers, and the success has warranted an
increase in research efforts over the past 5 years[55].
However, results continued to suggest that wider application of
the therapy should be approached with caution. The varying
range of tolerance levels emphasised how the individual allergy
profiles of each patient will lead to different responses to
therapy[83].
By 2011, the scale of the studies conducted had increased
significantly with safety and efficacy of peanut desensitisation
measured in an attempt to standardise the treatment for clinical
use[84][85]. In a multicentre randomised controlled trial
involving 28 children[85], 16/19 subjects undertaking OIT were
able to complete the 5000mg peanut flour challenge, compared
with median tolerance of 280mg in placebo groups. This
confirmed the ability of OIT to induce tolerance, although
the small sample size limited its application to a wider
population without further study. It is also important to consider
that 3/19 subjects were unable to complete the treatment due to
adverse effects, suggesting perhaps that some allergy profiles
are unsuited to the treatment. The immunological outcomes
measured in the study were comparable to other similar OIT
studies, with those who successfully achieve tolerance usually
showing an increased peanut serum-specific IgG4, decreased
peanut-specific IgE and an allergen-specific decrease in some
allergy-associated cytokines[84].
The latest notable peanut desensitisation trial by Anagnostou et
al (2014) is the largest clinical trial for peanut desensitisation to
date, with 99 children involved in a randomised controlled
crossover phase II trial[78]. After the first phase, 84% of the
active group showed daily tolerance (800mg peanut protein
ingestion) compared to 0% of the control group. In the second
phase the control group was given OIT, and showed similar
development of tolerance (91%). Secondary to developing
tolerance improvements on quality of life were also recorded.
However, the trial does not take into account long-term
effects of tolerance after immunotherapy, the understanding of
which is arguably crucial for implementation into clinical
practice. It should be noted that the study population was
limited to individuals aged 7-16, so extrapolation of data may be
restricted as a result.
Alternative administration routes have also been explored to
establish if there is a safer method for the therapy[86]. SLIT has
shown some promise; in a 2013 randomised DBPC multicentre
trial, 70% of participants were successfully desensitised to
496mg of peanut protein[87].
The safety advantages of SLIT compared to OIT is reported by
the World Allergy Organisation in their SLIT position
paper[75]. This is due to the typical dose of peanut protein used
being approximately 1000-times less in SLIT in comparison to
OIT[62]. In the aforementioned 2014 OIT trial, at least 81% of
participants experienced adverse effects (ranging from oral
pruritis and nausea to laryngeal oedema)[78], whereas in the
2013 SLIT trial only 37% experienced any side effects at
all[87]. Although peanut OIT has greater immunological
effects[86], SLIT may have particular clinical value for those
who are unable to tolerate OIT as it has fewer adverse events[62].
Conclusion
The Future of Immunotherapy
Significant knowledge has been gained regarding the
suppressive nature of the immune system and the roles of
particular cell types over the past decade[7][9][27]. Identifying
antibodies and mediators has aided our understanding of the
mechanism behind therapy and allows measurement of its
clinical effect[8][9][11]. However, some aspects of the regulatory
system still require study, particularly concerning the delivery of
therapy that can ensure long term changes and
maintained tolerance, as this remains a barrier to the ultimate
goal of immunotherapy in curing allergy[35][36][37][42].
Immunotherapy is an exciting field, with emerging routes of
administration currently under trial which aim to improve
efficacy and ease of use whilst minimising side
effects[58][61][62]. Despite reducing treatment duration and
increasing patient compliance, some show less effect than the
traditional routes, or even no benefit against placebo[60].
Research on dosing plans has also been conducted to maximise
therapeutic benefits, but results are often specific to certain
diseases and may not be transferable to other
allergies[29][30][34][35]. With more ongoing trials, new evidence
will hopefully be developed for improving treatments.
Allergic Rhinitis (AR)
Many studies have demonstrated the clinical effects of
immunotherapy to tackle AR; however, these benefits are
usually relatively small (~20% reduction in symptoms[65] or
1/3 of treated asthmatics being able to cease inhaled
corticosteroid use after a year[68]) and so do not have high
enough impact on patient experience to warrant its frequent
use. This, coupled with the cost of the treatment, may indicate a
redundancy in this treatment at its currently proven efficacy.
In 2004, data was compiled from numerous national sources to
gain understanding of the burden of allergic disease[88]. This
research demonstrated that not only was the UK the country
most affected by allergic symptoms in Europe, but that these
effects correlated with significant financial impact upon the
NHS. The majority of this financial burden was linked to
prescription of treatment (representing over 10% of the GP
prescribing budget), alongside GP consultations and hospital
admissions[88].
Despite being a generally non-life-threatening condition, the
cost related to AR sufferers may still be considered in terms of
working days lost due to symptoms plus any treatment
requirements, especially if they progress onto other related
conditions, such as asthma[70]. Immunotherapy has been proven
in one trial to reduce need for inhaled corticosteroids in asthma
patients; a treatment which is both costly and has many
associated risks[68]. Early intervention may be hugely beneficial
in preventing this 'allergic march', and therefore
avoiding further expense for both the individual and the
healthcare system[70].
Immunotherapy for AR may be one of the closest to routine
clinical use in the UK, with many other European countries
already
providing
this
disease-modifying
treatment
over symptom control[89]. However current efficacy would need
to be improved upon before routine clinical use would provide
both sufficient improvement to patients' quality of life as well
as financial benefits.
Peanut Allergy
The promising results from peanut desensitisation trials have
warranted huge attention not only from the NHS[90] but also
from the media[91], and have sparked complex debates
questioning whether or not this treatment is ready for clinical
practice[55]. Some reviews maintain that the risks of OIT are
greater than those of peanut avoidance, and believe not
enough is known about the topic of dosing regimens, patient
selection or large scale administration[92].
In addition, limited long term studies into the therapy means
there is a significant lack of evidence to suggest sustained
desensitisation is possible, and furthermore there are fears over
other long-term effects which may put those who receive the
treatment at long-term risk[93]. A review of peanut
immunotherapy by Anagnostou and Clark looked at several
studies involving longer-term outcomes, and concluded that
long-term tolerance to peanut does occur in a small proportion
of those receiving OIT but larger studies will be required to
fully tackle this question[94].
On the other hand, it has been argued that the potential benefit
of immunotherapy outweighs the risks associated with
desensitisation due to the extent of the negative effect on
quality of life that peanut allergies are shown to have[95]. The
same review also comments that there have been no significant
long-term unexpected reactions, suggesting that the fears over
long-term desensitisation are unjustified. This is of particular
interest when taking into account the fact that over half of
allergy-related deaths are due to peanut allergy[77]. In the USA,
a number of health centres currently offer desensitisation
programs, carried out at medical allergy centres[96].
In 1989, the Joint Task Force (JTF) on Practice Parameters
was formed with the aim to provide a comprehensive
evaluation of the current literature regarding food allergy
management and treatment. The parameter currently
recommends that OIT is not ready for clinical practice due to
insufficient evidence regarding its therapeutic benefit over the
risk of therapy[97], although it should be noted that current
research is progressing quickly with the hope that this therapy
will soon be available for routine use.
A Final Word
We thoroughly enjoyed this project as it allowed us to relate the
science of allergy to our own lives and personal
experiences. Having been exposed to positive media coverage of
allergen-immunotherapy, we were curious as to why it is not
routinely offered. However, this project has transformed our
perception
of
the complexity
of
treatment
development. Expanding our knowledge of the pathophysiology
of allergy allowed us to understand the complex nature of
allergic disease. Furthermore, by appraising the literature
surrounding
immunotherapy,
we
were
able
to
discern the barriers to implementation in clinical practice.
As future medical professionals we hope that with more
definitive research these barriers will be overcome
and implementation of immunotherapy into clinical practice will
become a reality for all allergic disease.
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