REVIEW ARTICLE

Iran J Allergy Asthma Immunol

March 2011; 10(1): 1-9.

A Review of Allergy and Allergen Specific Immunotherapy

Katayoon Bidad1,2, Mohammad Hossein Nicknam2, and Reza Farid3

1
Department of Immunology, Tehran University of Medical Sciences, Tehran, Iran
2
Molecular Immunology Research Institute, Tehran University of Medical Sciences, Tehran, Iran
3
Immunology Research Centre, Buali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran

Received: 28 October 2010; Received in revised form: 13 December 2010; Accepted: 20 December 2010

ABSTRACT

Since 20th century, when allergy was defined, an ongoing attempt for discovering the
mechanisms underlying it and its treatment began. Defining allergens as well as cells such as
regulatory T-cells and characterizing the antibodies involved in the pathogenesis (including
blocking antibodies) have helped very much towards a better understanding of the
immunologic process.
However, Allergen specific immunotherapy (SIT), as a specific curative treatment for
allergy also dates back to the beginning of the previous century and has progressed
considerably during these years. SIT similar to natural immunomodulation, directs the
immune response towards tolerance.
New strategies in this field, such as using recombinant allergens, T- and B-cell-epitope-
containing peptides, and DNA vaccination have shown promising results. Sublingual
immunotherapy, although not yet FDA-approved, as an alternative strategy in SIT has
demonstrated efficacy as well as safety.
Furthermore, allergen extracts, their standardization and their modification have also
been the focus of much research. Undoubtedly, specific immunotherapy is proven to be an
efficacious method to treat allergy, so its cost-effectiveness should be estimated in
developing countries in order to include it in the country's health priorities. Informing
physicians about the new anti-vaccination movement is also crucial.

Key words: Allergens; Allergen Immunotherapy; Allergy; Blocking Antibodies; T Cells

INTRODUCTION meaning, “change in the original state”.

The first report on specific immunotherapy goes
The term allergy was first used by von Pirquet in the back to the beginning of the 20th century (1911), when
year 1906 to describe harmful immune responses for Noon injected an extract of grass pollen into a person
the host. The word comes from the Greek word “alol”, whose allergic symptoms coincided with the pollination
of grass.1 At that time, it was believed that pollens
Corresponding Author: Reza Farid, MD; contain undefined toxins. Ten years later, allergen-
Immunology Research Centre, Buali Research Institute, Mashhad specific sensitivity was passively transferred by a
University of Medical Sciences, Mashhad, Iran. Tel/Fax: (+98 511)
8842 8014, E-mail: rfaridh@yahoo.com serum factor1 and it took several years until IgE and

Copyright© 2011, IRANIAN JOURNAL OF ALLERGY, ASTHMA AND IMMUNOLOGY. All rights reserved. 1
 K. Bidad, et al.

then IgG blocking antibodies were discovered. Today, T-cell Phenotypes in Allergic Response
by expansion of allergy epidemic all around the world, T cell is known to be the principle conductor of the
immunotherapy is widely used and the mechanisms allergic orchestra. The T-helper cell response is mainly
underlying allergy and immunotherapy are extensively the TH2 type which is mostly associated with the
investigated. New developments in this field and the allergic response. However, newly discovered cells also
emergence of Regulatory T-cells (Treg cells) and T contribute to the pathogenesis. In fact, the ratio of
helper 17 cells (TH17 cells) however have enlightened allergen-specific IL-10-secreting cells (Treg cells) to
the concepts in allergy and hypersensitivity and filled IFNγ-secreting cells (TH1 cells) and IL-4-secreting
the gap in the understanding of inflammatory cells (TH2 cells) and their continuous balance at the
processes.2 Furthermore, the implementation of good onset or during the course of response determines the
clinical practice (GCP) in the conduct of clinical trials outcome to be normal or develop allergic immune
on medicinal products for human use introduced by the response.6
Directive 2001/20/EC3 improved the evidence-based In atopic disorders, TH2 cells produce IL-4, IL-5
medicine and the researches in the field of and IL-137 which result in allergen-specific IgE
immunotherapy. production by B cells, eosinophil activation and
recruitment, mucous production, bronchial
What Is an Allergen? hyperreactivity and allergic tissue homing of TH2 cells.
Allergens are proteins in most cases and have two TH1 subset might lead to chronicity and effector phase
characteristics; they induce IgE responses in in allergic diseases. On the contrary, Treg cells inhibit
sensitization phase and a clinical response on the development of TH1 and TH2 cell responses.6 Treg
subsequent exposures (Figure 1). Despite the wide cells act by engaging inhibitory cell surface molecules,
investigations on allergens, their structures and their producing inhibitory cytokines, as well as cytolysis and
sequences, researches on their allergenicity still are disrupting metabolism.8
ongoing 4. Up to now, published data regarding TH17 cells
favor their role as proinflammatory by inducing
Physiopathology of Allergic Immune Responses proinflammatory cytokines (TNF-α, IL-1β, and IL-6)
Allergic immune response consists of sensitization and chemokines (CXCL1, 2 and 8), and neutrophil
and development of specific immune response toward recruitment.2 IL-17 has also been indicated as a marker
the allergen. During sensitization, the following events for allergy severity.9
occur: priming of allergen-specific CD4+ TH2 cells,
production of TH2 cytokines (IL-4 and -13), and thus Specific Immunotherapy (SIT)
class switching for IgE production, activation of Allergen-specific Immunotherapy which is also
endothelial cells, eosinophil migration to tissues, mast called allergen immunotherapy, hyposensitization
cell and basophile degranulation. Subsequent and therapy or desensitization, involves administration of
frequent exposures lead to changes in target organs and increasing concentrations of antigen-specific extracts to
remodeling.5 allergic patients with the goal of inducing a state of
immunologic tolerance.10 The aim is to alleviate
symptoms during exposure to the allergen. It is an
FDA-approved, clinically effective method and induces
long-term remission of allergic rhinitis and allergic
asthma, with improvement in clinical symptoms.11-13
Successful immunotherapy results not only in the
increase of allergen concentration necessary to induce
immediate or late-phase reactions, but also in the
decreased responses to nonspecific stimulation.14
Therefore, in contrast to symptomatic treatment, it can
reduce the likelihood of developing additional
Figure 1. Features of allergens contributing to sensitizations by interrupting the so-called “atopic
allergenicity march” and patients may benefit from persistence of

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 Allergy and Allergen Specific Immunotherapy

alleviation of clinical symptoms.11,14-16 However, only Mechanisms of SIT

less than 5% of patients choose immunotherapy as a Although due to different methodologies in
treatment option for their allergy.16 As allergen different studies, the exact mechanisms of SIT have not
immunotherapy reaches its 100th anniversary, attempts been fully described, some features seem to be in
for safer methods and more convenient procedures common. These include: change of antigen presenting
continue.14 cell (APC) function, T cell responses, immunoglobulin
responses and response of other cells.1
Natural Immunomodulation APCs in SIT. APCs and especially dendritic cells
Naturally occurring immunomodulation can induce (DCs) initiate the immune response by delivering the
humoral and cellular features that we try to imitate in environmental signals to other cells. Their lineage and
SIT, as in the case of beekeepers. Beekeepers’ their own maturation status can influence the ultimate
lymphocytes do not proliferate in response to allergens result to be peripheral tolerance or immunity. While
and do not produce IL-2.17 Heavily stung beekeepers performing SIT, since we do not have pro-
have specific IgE as well as positive prick test for bee inflammatory signals and innate immunity is not
venome, but their partial tolerance is due to the triggered, DCs show partially mature phenotype, thus
existence of bee venom specific IgG and mainly IgG418 they have tolerogenic interaction with lymph node T
and allergen-specific IL-10-secreting T cells.19,20 The cells. As a result, IL-10 secreting Treg cells
level of specific IgG4 primarily reflects exposure and develop.23,24
correlates with the number of annual stings and years T-cell responses in SIT. Having a small number of
spent in bee-keeping.6 It should be kept in mind that the Treg cells and a large number of TH2 cells results in an
beekeepers are at risk of bee-venom allergy and allergic response. It has been shown that SIT can
anaphylaxis if they have fewer than 10 annual stings restore the activity of allergen-specific IL-10-secreting
and high serum-specific IgE and low serum-specific Treg cells.5,20,25-27
IgG. On the other hand they can better tolerate SIT affects T-cell responses to allergen by
immunotherapy.18 employing several mechanisms, including the
As another example, exposure to large following: by increasing the allergen-induced ratio of
concentrations of animal dander in children also TH1 cytokines to TH2 cytokines, by inducing epitope-
induces IL-10 and IgG4 production and protection from specific T-cell anergy that can be blocked by
allergy.21 This IgG can compete with IgE for allergen neutralization of IL-10, by generating allergen-specific
binding and can reduce IgE-mediated degranulation of Treg cells that can suppress the responses of effector T
mast cells and basophils.1 cells and by increasing the production of cytokines with
Recent studies imply the possibility that maternal regulatory activity.1
farm exposure and consumption of farm milk can One study based on mathematical modeling of
increase microbial exposure which might lead to a form allergy and specific immunotherapy has suggested that
of natural immunotherapy. In this setting, the the crucial event in immunotherapy is proliferation of
environmental factors redirect the immune response to Treg cells and suppression of Th2 cells. High-dose
aeroallergens from Th2- to Treg-responses.22 injections with short intervals can augment these
effects.28
Sequential Events in SIT Immunoglobulin responses in SIT. IgG blocking
In allergen-specific immunotherapy, very early antibodies compete with IgE for allergen binding.5,10,20
effects are attributed to mast cell and basophile Their functional activity rather than the absolute
desensitization (very early desensitization effect). amount determines the outcome. Allergen-specific IgG
Intermediate effects are due to changes in allergen- might be directed against the same epitopes as allergen-
specific T cells (generation of Treg cells and peripheral specific IgE (blocking the effect of IgE), against
T cell tolerance), and late effects are related to B cells different epitopes (no effect) and in some cases it can
and IgE (modulation of allergen-specific IgE and IgG amplify cross-linking of allergen-IgE-FcεRІ complexes
subtype responses) and also mast cells, basophils, and (increasing effector function and adverse effects).29
eosinophils (suppression of effector cells and SIT-induced IgG in addition to competing with IgE
inflammatory responses).5 and preventing degranulation of mast cells and

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 K. Bidad, et al.

basophils, can inhibit IgE facilitated allergen Allergens

presentation to T cells, thus decreasing late-phase Recombinant Allergens and Allergen Derivatives
reactions, and can reduce the number of allergen- Using recombinant/engineered allergens, possibly
specific memory B cells by preventing activation modified by site-directed mutagenesis, represents an
signals for affinity maturation, memory induction and exciting alternative approach which is directed at
differentiation.1,30 In addition to the above-mentioned maintaining the immunogenicity of a vaccine while
mechanisms, IgG can also deliver a negative inhibitory reducing the capacity to bind allergen-specific IgE.11,35
signal to mast cells via FcγRIIB.31 However, it has The results related to their use, hold promise that
recently been shown that IgG induction alone is not recombinant allergen–based immunotherapy will
sufficient to desensitize the patients.32 improve current immunotherapy practice and may open
SIT induces ten to hundred fold increase in IgG1 possibilities for prophylactic vaccination,36 although no
and -4 and a modest increase in IgG2. It has been clinical efficacy has been documented yet. Side effects
observed that IgG4 exerts inhibitory effects on binding occurring in this type of immunotherapy highlight the
of IgE- FcεRII complexes on B cells33 and this might necessity of determining maximum tolerated dose in
be due to its unique structural characteristics of its these molecules which are thought to be
hinge region and its ability to separate and re-pair hypoallergenic.32
(forming monomeric antibodies)6,34 and also the fact
that it does not fix complement. Furthermore, IL-10 T-cell-epitope Containing Peptide Approaches
generated during SIT not only elicits anergy in T cells Peptide fragments corresponding to T cell epitopes,
but also decreases IgE: IgG4 ratio in peripheral blood.20 have been used in experimental models of allergy and
Interestingly, IFNγ suppresses IgG1 production while autoimmunity. Their secondary and tertiary structures
increases IgG2. Recently, it has been shown that and their sizes, help them to lessen cross-linking of
allergen specific IgA in response to TGFβ increases IgE. Adverse events occur as a result of residual IgE
during SIT.1 reactivity in larger peptides and activation of allergen-
Changes in other cells. Allergen-specific specific affector T cells at high peptide doses.
immunotherapy can reduce the number of tissue mast Therapeutic effects are caused by induction of allergen-
cells as well as eosinophils,26,30 while decreasing the specific Treg cells.37 These vaccines can also be taken
mediator release in mast cells, basophils and orally to induce mucosal immunization as a
eosinophils. Release of proinflammatory cytokines also replacement for systemic inoculation.38
decreases during the course of SIT. IL-10 is the
cytokine responsible for downregulation of eosinophil B-cell-epitope Containing Approaches
activity, causing reduced proinflammatory cytokine Synthetic peptides with the potential to induce the
release, inhibition of GM-CSF production and CD-40 production of blocking IgG have been defined from
expression, ultimately eosinophil cell death.26 IgE-binding epitope-mapping data and from analysis of
the three-dimensional structure of an allergen.
New Strategies in SIT Vaccination of animals with such peptides has shown
To standardize SIT, many strategies have been success.1
employed and these attempts would try to maximize the
safety as well as efficacy (Table 1).

Table 1. Alternative strategies in Allergen Extract Immunotherapy

Allergens Delivery routes Extracts

- Adjuvants and carriers - Epicutaneous/ transcutaneous - Recombinant allergens
- Allergoids/polymerized extracts - Intralymphatic - Frangments or folding variants of recombinant allergens
- Immunostimulatory sequences - Subcutaneous - T-cell-epitope containing peptides
- Fusion proteins - Local nasal - B-cell-epitope containing peptides
- Oral - DNA vaccines
- Sublingual-swallow
- Sublingual-spit

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 Allergy and Allergen Specific Immunotherapy

DNA Vaccination solutions, tablets or gastroresistant capsules are

New developments in this field include plasmid swallowed. In sublingual swallow technique antigen is
injection, oral delivery of genes using chitosan-DNA held for 1 to 2 minutes under the tongue and then is
nanoparticles and replicon-based DNA vaccines swallowed, while in sublingual spit technique the
(targeting DCs). Allergen-encoding DNA induces antigen is spit out after 1 to 2 minutes under the
allergen-specific TH1-cell response but has the potential tongue.43
to cause anaphylaxis because of systemic production of Sublingual pharmacokinetics of non-injection
allergen by transfected cells.1 routes do not seem to differ between allergic and
healthy individuals or between modified and native
Delivery Routes allergens. The rapid binding of allergen to oral mucosa
Epicutaneous/Transcutaneous Immunotherapy is the reason why sublingual-swallow and –spit
Transcutaneous immunization (TCI) or technique show no significant differences in local
epicutaneous immunotherapy (EPIT) refers to the pharmacokinetics.43 The differences in sublingual and
application of vaccines to the skin. By using subcutaneous methods may be due to differences
microneedle or needle-free patches, antigens along with between oral APCs and Langerhans cells and their skin
adjuvants are delivered to the potent APCs of the skin counterparts.44 However; similar to subcutaneous
and also allergen specific IgE on Langerhans cells. immunotherapy, sublingual method in allergic subjects
These antigens are subsequently delivered to T cells. causes a reduction in proliferative responses of T cells,
Keratinocytes also play an active role by creating an their cytokine production, in ICAM-1 expression on
inflammatory environment favoring the induction of epithelial cells, the number of eosinophils and
allergy-protective immune responses. This method, neutrophils, induction of systemic Treg cells, an
with shorter duration and lasting effects, so far has increase in IL-10 production, and decreased bronchial
found to be efficacious and safe. Extensive clinical reactivity to methacoline. It also causes antigen-
trials are needed to support the preliminary findings specific IgE decrease, early rise in IgG1, late increases
and optimize the delivery systems and adjuvants used.16 in IgG4. The majority of publications comparing active
sublingual immunotherapy with placebo or controls
Intralymphatic Immunotherapy showed efficacy of this method for rhinitis,
In an attempt to decrease the frequency of allergen conjunctivitis, and/or asthma. Contrary to subcutaneous
administration, Senti et al, have used the intralymphatic immunotherapy that has a high potential for severe
approach for allergen immunotherapy. In a randomized reactions, sublingual route has minimal risk.22,13,45 To
(not blinded) controlled trail, allergens were delivered date, no severe or life-threatening adverse events have
via superficial inguinal lymph nodes under ultrasound been reported and the majority of events (asthma
guidance. The method was proven to be safe and exacerbation, rhinoconjunctivitis, oral cavity pruritis,
effective but future investigations are needed to throat irritation, rhinitis, itchy eyes, nausea, and GI
approve the method.13,16,39,40 complaints) have been mild and self-resolving
requiring symptomatic medications or dose-
Non-injection Immunotherapy adjustments.43 The safety of this technique will likely
In order to increase the safety of immunotherapy provide increased opportunities for higher risk patients,
and provide an easier administration, non-injection such as asthmatic persons and children under the age of
routes such as nasal, oral, sublingual-swallow and 5.43,44 SLIT can be used co-seasonally, pre-seasonally
sublingual-spit techniques were developed. In nasal or continuously.13 Furthermore, the effectiveness of this
immunotherapy, an aqueous solution or powder in method in allergic rhinitis and asthma and also for
capsules (which are to be broken later), are sprayed into prevention of new sensitizations is noteworthy46
the nose through an appropriate devise to avoid (Table 2).
inhalation into the deep airways. Thus, by introduction
of sublingual immunotherapy, the use of nasal Allergen Extracts for Immunotherapy
immunotherapy is declining.41 Allergen extracts are used for diagnosis and specific
In oral immunotherapy (SLIT), which is shown to immunotherapy of allergies. These extracts contain
be effective and relatively safe,42 antigens in aqueous allergenic and non-allergenic constituents.

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 K. Bidad, et al.

Table 2. Comparison of subcutaneous and sublingual immunotherapy

Topics Sublingual immunotherapy Subcutaneous immunotherapy

Administration Oral Injection
APCs involved Oral APCs and Langerhans Cells Skin APCs and Langerhans Cells
Efficacy ++++ ++++
Safety ++++ +++
Severe adverse reactions - +
APC: Antigen Presenting Cell

The concentration of allergens is influenced by inhibit the development of allergic responses in

biovariability, different production processes and animals.50 Carrier Molecules combined to allergens
genetic diversity of the affected patients.47 The route of such as virus-like particles are under investigation for
immunotherapy also affects antigen preparation. For the design of new vaccines. These highly-immunogenic
example, in sublingual immunotherapy, antigen is first molecules are fused to allergens with low or no
exposed to oral mucosa and due to limited absorption allergenicity. This technology might be applied to any
of allergens from mucosal surfaces, high-dose regimens allergen with supposedly long-lasting effects.32
likely facilitate capture of allergens by sentinel
dendritic cells, which represents a critical step to Allergoids/Polymerized Extracts
induce adequate and long-lasting T cell responses.44 These approaches can reduce allergenicity of the
Thus, the need for standardization of these extracts in extract while retaining its immunogenicity.
order to avoid large differences among different
manufacturers and to ensure a consistent composition Immunostimulatory Sequences
and potency are essential and are at most Synthetic cytosine phosphorothionate guanosine
importance,30,44,47 DNA chains, when covalently linked to allergens, have
In recent years, for each medicinal product, the advantage of being recognized by toll-like receptor
including allergen products, quality, safety and efficacy 9 and directing the response toward a regulatory and
have to be proven by the manufacturer to obtain a TH1 response9,45 and also of sterically interfering with
marketing authorization (MA).48 Allergen products the reaction of IgE with the allergen, thus reducing its
according to Directive 2001/83/EC refer to "any allergenicity.
medicinal products, administered to human beings, TH1 responses to allergens can be augmented by
which are intended to identify or induce a specific direct linkage of immunostimulatory sequence of DNA
acquired alteration in the immunological response to an (ISS) to the protein. Favorable results have been
allergizing Agent". A number of guidance documents obtained by this method.45
exist that concentrate on specific aspects of allergen
products such as "the Note for Guidance on Allergen Fusion Proteins
Products" and "the Monograph on Allergen Products of Mast cells and basophils express FcγRIIb, which
the European Pharmacopoeia".48 contains an immunoreceptor tyrosine-based inhibition
motif within its cytoplasmic tail. Aggregating FcγRIIb
Alternatives for Currently Available Extracts to the major IgE receptor, FcεRI, leads to inhibition of
Adjuvants and Carriers FcεRI signaling.14
Use of adjuvants such as alum and more recently L-
tyrosine reduce the rate of dissemination from the CONCLUSION
injection site and reduce systemic reactions. Another
approach is to provide TH1 adjuvant effects as with Specific Immunotherapy for respiratory allergy and
monophosphoryl lipid A.49 The use of liposomes to severe allergic reactions is used for about one century
encapsulate allergens for SCIT has been proposed and and there is now solid documentation of its efficacy
in one study showed clinical efficacy compared with and safety.30,51
traditional vaccines as well as a good safety profile.11 Subcutaneous immunotherapy is generally available
Mycobacterium adjuvants have also been shown to in Europe, the United States and in most countries.

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 Allergy and Allergen Specific Immunotherapy

Many extracts are standardized either biologically or member states relating to the implementation of good
immunologically. The clinical efficacy of SCIT is now clinical practice in the conduct of clinical trials on
well established11 and regarding safety, though medicinal products for human use. Med Etika Bioet
systemic reactions are not frequent, careful 2002; 9(1-2):12-9.
administration is recommended.11,52 4. Akdis CA. Allergy and hypersensitivity: mechanisms of
Sublingual immunotherapy is currently marketed in allergic disease. Curr Opin Immunol 2006; 18(6):718-
several European countries and is also available in 26.
other countries (eg, Argentina, Brazil, the Gulf States, 5. Akdis M, Akdis CA, Mechanisms of allergen-specific
and South Africa). Extracts may be standardized either immunotherapy. J Allergy Clin Immunol 2007;
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local and self-limiting side effects. However, there still regulatory cells and more. Curr Opin Immunol 2006;
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SLIT. 7. Tavakkol Afshari J, Farid Hosseini R, Hosseini
Despite the wide administration of allergen specific Farahabadi S, Heydarian F, Boskabady MH,
immunotherapy in developed countries, its use in Khoshnavaz R, et al. Association of the Expression of
developing countries such as Iran is still limited. Few IL-4 and IL-13 Genes, IL-4 and IgE Serum Levels with
numbers of specialists in the field of allergology and Allergic Asthma. Iran J Allergy Asthma Immunol 2007;
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