Biomedicine & Pharmacotherapy 61 (2007) 29e33

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Dossier : Allergy

Mechanisms of immunotherapy in allergic rhinitis

Nivenka P. Jayasekera, Tudor P. Toma, Andrew Williams, K. Rajakulasingam*
Department of Respiratory Medicine/Allergy, Homerton University Hospital NHS Foundation Trust, Homerton Row, London E9 6SR, UK
Received 21 September 2006; accepted 22 September 2006
Available online 5 December 2006

Abstract

Allergic rhinitis is a common condition, but many people still experience suboptimal control of symptoms despite measures such as allergen
avoidance, intra-nasal steroids and antihistamines. Specific immunotherapy (SIT) has been used for many years, but though many studies show
clinical efficacy, its mechanism of action is still not clearly understood. Earlier studies showed changes in antibodies and it may be that SIT
works through mechanisms that alter the ratio of ‘protective’ IgG4 to ‘pro-allergenic’ IgE. Other studies have shown a reduction in eosinophil
migration to nasal mucosa as well as a reduction in inflammatory mediator release including basophil histamine release. More recent studies
have proposed that SIT works through inhibition of T-helper 2 lymphocytes (Th2) which preferentially produce cytokines that promote allergic
responses. SIT may cause a deviation from Th2 to Th1 (T-helper 1 lymphocytes) or may induce T-regulatory cells (T-regs) which inhibit Th2
responses directly or through inhibitory cytokines.
Ó 2006 Elsevier Masson SAS. All rights reserved.

Keywords: Allergic rhinitis; Specific immunotherapy (SIT)

1. Introduction failed to respond to conventional therapies in allergic rhinitis.

SIT has a long lasting benefit and has been shown to be cost-
Allergic rhinitis is the most common allergic condition effective as well [2,3]. This article discusses the possible mech-
affecting over nine million people in the UK and the prevalence anism(s) of SIT based on the published literature evidence.
is increasing. It can affect people of all ages, sexes, social and
ethnic groups and has an impact on their quality of life as well
as healthcare utilisation. In a survey conducted by Allergy UK 2. Mechanism of allergy
in 2005 [1], 49% of those who were surveyed reported that their
rhinitic symptoms affect their school/work moderately to se- An allergen can induce both an immediate type I and a de-
verely. Eighty percent of those also said that it affects how layed type IV hypersensitivity reaction [4e6]. The immedi-
they spend their social time with 76% saying that it limits their ate allergic response results in IgE dependent mast cell and
choice of outdoor activities. Some patients had spent more than blood basophil activation, preformed mediator release e.g.
three hundred pounds in a year trying to make their home histamine and newly generated synthesis of mediators from
allergy free [1]. Therefore, there is a need to find more effective the arachidonic acid pathway e.g. leukotrienes and prosta-
therapies for allergic rhinitis. Specific allergen immunotherapy glandins. This can lead to acute clinical symptoms such as
(SIT) has been shown to be effective in patients who have wheeze, urticaria, sneezing, rhinitis and conjunctivitis
(Fig. 1).
Type IV hypersensitivity is a delayed phenomenon and can
occur 6 to 24 h later. Allergen is taken up and processed by
* Corresponding author. Tel.: þ44 (0)20 8510 7769; fax: þ44 (0)20 8510
7731. antigen presenting cells (APC) e.g. macrophages, dendritic
E-mail addresses: [email protected] (N.P. Jayasekera), cells and Langerhans cells which present the antigen to T lym-
[email protected] (K. Rajakulasingam). phocytes. This can lead to production of Th2 CD4þ type

0753-3322/$ - see front matter Ó 2006 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.biopha.2006.09.013
30 N.P. Jayasekera et al. / Biomedicine & Pharmacotherapy 61 (2007) 29e33

Key B cell – B lymphocyte cell, APC – antigen presenting cell, Th2 – type 2 T helper cell.

Histamine,
leukotrienes, Acute Allergic
Mast IgE prostaglandins Reaction
Cell
- Wheezing
- Urticaria
- Sneezing
IL5 - Rhinirrhoea
IL4
- Conjunctivitis

B
Allergen
Cell Eosinophil
Basic
proteins,
leukotrienes
IgE IL4 , PAF
production IL5

Mast Chronic Allergic

Reaction
Cell
- Further wheezing
APC Th2 - Chronic
Histamine nasal block
Histamine releasing factor cytokines - Eczema

MHC II
molecule T Cell
Receptor

Fig. 1. Mechanism of early and chronic allergic symptoms.

T cells which express interleukin (IL)-4 and IL-5 which in turn 4. Mechanism of immunotherapy
have a direct effect on IgE producing B lymphocytes and a
variety of inflammatory cells e.g. mast cells, basophils and Although it is generally accepted that SIT reduces symp-
eosinophils, thus causing a delayed inflammatory response toms of allergic reactions, the precise molecular mechanism
and chronic symptoms in cases of persistent exposure (Fig. 1). behind this improvement is not clearly understood. Various
studies have observed changes in antibodies, cellular events
and cytokines before and after treatment which may explain
how SIT works.
3. Management

Currently, patients with allergic rhinitis are treated symp- 4.1. Changes in antibodies
tomatically with anti-histamines, topical steroids and leuko-
triene receptor antagonists together with measures to avoid Earlier studies by Cooke et al. [9] and Loveless [10]
allergens [2,3]. Some patients may experience side effects showed that patients with allergy receiving SIT had a rise in
while on going prescriptions and allergy avoidance can be IgG antibody levels. A study by Lichtenstein et al. [11] dem-
costly as well as impractical. Symptom control may still onstrated that an immunotherapeutic dose that fails to induce
be suboptimal with less than 40% of patients with seasonal an increase in IgG antibody is unlikely to result in a significant
allergic rhinitis reporting good symptom control in UK general improvement in symptoms. IgG antibody titres however do not
practice [7]. necessarily predict clinical success in individual patients and
Specific allergen immunotherapy involves weekly adminis- a causal relationship has not been proven. In a number of stud-
tration of gradually increasing subcutaneous, sublingual or ies, subsets of patients with good clinical relief had no sig-
intranasal doses of allergen to which the patient is sensitive nificant IgG antibody production and some patients with
to in order to improve symptoms associated with subsequent increased IgG antibody titres showed no clinical response [12].
exposure. It is the only therapy to date that can affect the nat- Peng et al. showed that IgG1 is the dominant immunoglob-
ural course of allergic disease and has been shown to be effec- ulin response during the early course of immunotherapy and
tive in the treatment of allergic rhinitis/conjunctivitis, allergic IgG4 begins to appear in significant quantities after prolonged
reactions to stinging insects and allergic asthma in many dou- immunization [13]. It has been suggested that IgG4 antibodies
ble blind randomized studies [2,3,7]. It may also prevent the are associated with protection by binding to the allergen,
development of asthma in patients with allergic rhinitis as thereby preventing its interaction with allergen specific IgE at-
well as further allergen sensitisations [2,3,8]. Currently it is tached to effector cells or by forming an IgG4eallergeneIgE
licensed in the UK for allergic rhinitis and allergic reactions complex which inhibits IgE triggering. However some studies
to insect venom. have failed to confirm these findings and the increase in
 N.P. Jayasekera et al. / Biomedicine & Pharmacotherapy 61 (2007) 29e33 31

allergen specific IgG4 levels has not been shown to be closely a consequence, even though the overall levels of allergen-
linked to the clinical response [14]. On the other hand, a more specific IgG may not be significantly modified, the set of
recent study by Nanda et al. demonstrated the early predictive bee venom allergen epitopes that are recognized by IgG is
value of SIT-induced specific IgG4 increase in the case of SIT changed. Thus it appears that SIT success may be better cor-
for cat allergy rhinitis [15]. Indeed, in this study a statistically related with changes in IgG4/IgE ratios and the more subtle
significant rise of cat allergen-specific IgG4 levels (but not the alterations in antibody binding specificities rather than with
increase in total IgG) measured after 5 weeks of SIT was cor- overall IgG titres that can be measured in the serum.
related with the decrease of clinical symptoms scores mea-
sured after one year of SIT. 4.2. Changes in effector cells
Lichtenstein et al. demonstrated that there was a fall in the
usual seasonal rise in IgE antibody which has been shown to The late phase reaction is dependent on the recruitment of
be inversely correlated with the rise in IgG [16]. There is various cells including eosinophils, neutrophils and basophils
also, after an initial rise, a slow decline in the level of specific into the inflammatory site where they release inflammatory
IgE in patients with allergy during the course of SIT [16]. An- mediators that perpetuate the inflammatory response. Studies
other reported effect of SIT is reduced levels of the soluble low have demonstrated that after exposure to allergen, eosinophil
affinity receptor for IgE, CD23, known to be of importance in migration into nasal secretions is significant by 2 to 4 h and
the regulation of IgE antibody production [17,18]. continues to increase up to 8e10 h. A similar though not sig-
Platts-Mills et al. have shown that patients with ragweed nificant increase is seen with basophils. SIT has been shown to
and grass allergy had a seasonal increase in specific IgA and reduce allergen induced eosinophil migration and blunt the
IgG antibodies in nasal secretions. SIT with ragweed in these typical seasonal influx of eosinophils into the nasal mucosa
patients is associated with a further increase in IgG and IgA [22]. Majchel et al. showed that SIT prevented the increased
antibodies. However, no relationship has been demonstrated responsiveness of the nasal mucosa to histamine that is usually
between these findings and clinical improvement [19]. seen in allergic patients challenged during the ragweed-pollen
A provisional explanation for these apparently contradic- season [23].
tory data regarding the role and predictive value of allergen- Studies have shown that in most allergic patients undergo-
specific IgG4 in SIT can be proposed when considering the ing SIT, there was a decrease in basophil histamine release
findings of Akdis et al. [20] and those by Michils et al. [21] [24,25]. This was associated with a marked reduction in clin-
for bee venom immunotherapy. In the study by Akdis et al. ical symptoms. However, there were some exceptions with
it was shown that successful SIT initially increases both the some patients experiencing improvement in symptoms but
‘pro-allergenic’ IgE and the ‘protective’ IgG4, but the overall with high basophil reactivity [24,25]. A study by Creticos
bee venom-specific IgE/IgG4 ratio is decreased as a conse- et al. showed that after nasal provocation with ragweed in
quence of SIT. Michils et al. found that ultra-rush SIT induces ragweed allergic patients, significantly fewer patients in the
early alterations of allergen binding by specific IgG antibodies immunized group experienced clinical symptoms or demon-
as early as 12 and 24 h after its initiation [21]. As strated inflammatory mediator release in their nasal secretions

Immunotherapy
(High dose Ag) B
IL4 cell

Natural
exposure
(low dose Ag)
Th
+ APC Allergy
2
IgE

IL5 Eo
Th1 Tr

IFN γ IL10 TGF β Key

Allergic response to natural exposure

Negative feedback
IgG IgG4 IgA
Ag – antigen, APC – antigen presenting cell,
IFN – interferon, Ig – immunoglobulin, IL –
interleukin, TGF – transforming growth
factor, Th – T helper cell, Tr – T regulatory
cells

Fig. 2. Schematic diagram of mechanism of immunotherapy by altering T cells and cytokine profile.
32 N.P. Jayasekera et al. / Biomedicine & Pharmacotherapy 61 (2007) 29e33

Table 1 allergy including allergic rhinitis, its mechanism of action is

Major immunological changes during immunotherapy not clear. Studies so far have helped us to appreciate that
[ in IgGdinitially IgG1 then IgG4 SIT probably modulates and affects many different immuno-
Initial [ in IgE followed by slow decline logical and non-immunological processes (Table 1) and that
Blunting of usual [ of seasonal IgE
[ IgG and IgA in nasal secretions
clinical improvement is a consequence of different mecha-
Y effector cells and mediator release nisms over time which may vary in different groups or individ-
Y of Th2:Th1 activity uals. Further research into the mechanism of action may lead
Induction of T regulatory cells not only to more efficacious therapies with minimal side
effects, but also to a better understanding of airways disease
in general.
including histamine, TAME-esterase, prostaglandins and leu-
kotrienes [26].
Acknowledgements
4.3. T-cell changes
We thank Dr Victor Turcanu, Department of Asthma and
More recent studies have focused on the effects of SIT on Allergy, Kings College, London, for the editorial comments
allergen specific T-cell responses and cytokine production made when we prepared the manuscript.
[2] (Fig. 2). Thus it has been proposed that SIT acts by altering
the ‘balance’ between the allergic T-cell responses (generated References
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