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Novel Routes for Allergen
Immunotherapy
Safety, Efficacy and Mode of Action
Philippe Moingeon; Laurent Mascarell
Posted: 04/10/2012; Immunotherapy. 2012;4(2):201-212. © 2012 Future Medicine Ltd.
Abstract and Introduction
Abstract
Allergen immunotherapy is the only curative treatment of IgE-mediated type I respiratory allergies.
Subcutaneous immunotherapy (SCIT) is used as a reference therapy and has transformed allergic
treatments; it improves symptoms (asthma and rhinitis) as well as the quality of life of patients. SCIT
requires repetitive administration and carries the risk of severe systemic adverse effects, including
anaphylaxis. Sublingual immunotherapy is now a valid noninvasive alternative to SCIT, as a safe and
efficacious treatment for respiratory allergies. In this article, we compare various routes of allergen
immunotherapy, including SCIT and sublingual immunotherapy, as well as more exploratory routes
currently under investigation (i.e., intralymphatic, epicutaneous, intranasal and oral). We discuss their
respective advantages, as well as their foreseen modes of action.
Introduction
Last year, we celebrated the 100th anniversary of the first successful studies of allergen immunotherapy
(AIT) performed on patients with hayfever.[1,2] Whereas the subcutaneous route is still a reference,
tolerance induction via alternative routes has raised considerable interest over the last three decades.
Importantly, sublingual immunotherapy (SLIT) is the only approach established as a valid noninvasive
alternative to the subcutaneous route for immunotherapy (SCIT). SLIT is safe and efficacious for
promoting allergen-specific tolerance,[3–10] as demonstrated by multiple double-blind, placebo-controlled
(DBPC) Phase III studies conducted in large cohorts of adults and pediatric patients allergic to grass pollen
or house dust mite (HDM). Besides the sublingual route, other routes of administration are being explored,
including the intralymphatic, epicutaneous, intranasal and oral routes, with some encouraging results in
terms of immunogenicity and clinical efficacy. This review provides an update on those various AIT
approaches, with a specific emphasis of their modes of action.
Tolerance Induction by Parenteral Routes of Administration
SCIT has been shown to be effective in decreasing both immediate and delayed symptoms, as well as the
consumption of medication in patients with type I allergies to insect venom, HDM, grass and tree pollens,
molds or animal dander ( Table 1 ).[11–17] The application of SCIT is limited by several drawbacks,
including the need for repeated injections over several years, and the risk of anaphylaxis, which is rare but
potentially life-threatening.
Table 1. Comparative properties of parenteral routes of allergen immunotherapy.
Route
Allergens
Clinical efficacy
Immune mechanisms
Ref.
Epicutaneous
Grass pollens,
HDM and food
allergens (cow's
milk, egg and
peanut)
Used as natural
extracts onto intact
or tape-stripped
skin
Amelioration in nasal
symptoms (grass
pollen)
Well tolerated with
minor local eczematous
reactions (grass pollen
and cow's milk)
Need for efficacy
studies in humans
No immunological
change in humans
Decrease in AHR,
eosinophils in BAL and
Th2 responses in mice
(OVA, grass pollen,
HDM and peanut)
[23–
27,85,86,105]
Excellent efficacy to
reduce asthma and
rhinoconjonctivitis
symptoms, as well as
drug consumption in
patients allergic to
HDM, pollen (grass
and tree), insect venom
and cat dander
Need for medical
supervision and risk of
anaphylaxis
Products prepared for a
patient on the basis of
the physician's
prescription – so-called
named-patient products
Decrease in
inflammatory mediators
(i.e., histamine, N-αtosyl L-arginine methyl
ester esterase, kinins,
PGD2 and
myeloperoxydase) and
migration of mast cells,
eosinophils and
basophils within target
organs (skin, nose and
lung)
Increase in seric IgG4s
(blocking antibodies)
Increase, then
progressive decline of
seric IgEs
Decrease in Th2
responses and induction
of Th1s and Tregs (both
systemic and local)
[11–
17,117,118,125–
131,133,134]
Pollens (grasses,
ragweed, birch,
Parietaria and
olive), HDM, cat
dander and
venoms
Used as natural
biological extracts,
allergoids,
recombinant
Subcutaneous
proteins (Bet v 1,
Phlp-1, -2, -5 and 6), purified natural
allergens (Amb a
1) or peptides (Fel
d 1 and PLA A2)
associated with an
adjuvant (e.g.,
CaPO4, alum or
MPL)
AHR: Airway hyper-responsiveness; BAL: Bronchoalveolar lavage; HDM: House dust mite; MPL:
Monophosphoryl lipid A; OVA: Ovalbumin; PGD2: Prostaglandin D2; PLA A2: Phospholipase A2.
Clinical Trials With Intralymphatic Allergen-specific Immunotherapy
Intralymphatic administration consists of the direct injection of the allergen into the lymph nodes. It was
initially tested to enhance protective immunity against viruses and tumors using vaccines based on proteins,
peptides, naked DNA or tumor cells.[18–20] As a potential alternative to SCIT, intralymphatic allergenspecific immunotherapy (ILIT) is now being investigated in humans in order to shorten the immunization
scheme with low doses of allergen extracts (with a 100–1000-fold reduction when compared with SCIT),
while maintaining efficacy. Studies in clinical trials have provided interesting results since ILIT with a
reduced number of allergen shots and doses demonstrates some efficacy (i.e., better tolerance to allergen
challenge) ( Table 1 ).[21]
Table 1. Comparative properties of parenteral routes of allergen immunotherapy.
Route
Allergens
Clinical efficacy
Immune mechanisms
Ref.
Epicutaneous
Grass pollens,
HDM and food
allergens (cow's
milk, egg and
peanut)
Used as natural
extracts onto intact
or tape-stripped
skin
Amelioration in nasal
symptoms (grass
pollen)
Well tolerated with
minor local eczematous
reactions (grass pollen
and cow's milk)
Need for efficacy
studies in humans
No immunological
change in humans
Decrease in AHR,
eosinophils in BAL and
Th2 responses in mice
(OVA, grass pollen,
HDM and peanut)
[23–
27,85,86,105]
Excellent efficacy to
reduce asthma and
rhinoconjonctivitis
symptoms, as well as
drug consumption in
patients allergic to
HDM, pollen (grass
and tree), insect venom
and cat dander
Need for medical
supervision and risk of
anaphylaxis
Products prepared for a
patient on the basis of
the physician's
prescription – so-called
named-patient products
Decrease in
inflammatory mediators
(i.e., histamine, N-αtosyl L-arginine methyl
ester esterase, kinins,
PGD2 and
myeloperoxydase) and
migration of mast cells,
eosinophils and
basophils within target
organs (skin, nose and
lung)
Increase in seric IgG4s
(blocking antibodies)
Increase, then
progressive decline of
seric IgEs
Decrease in Th2
responses and induction
of Th1s and Tregs (both
systemic and local)
[11–
17,117,118,125–
131,133,134]
Pollens (grasses,
ragweed, birch,
Parietaria and
olive), HDM, cat
dander and
venoms
Used as natural
biological extracts,
allergoids,
recombinant
Subcutaneous
proteins (Bet v 1,
Phlp-1, -2, -5 and 6), purified natural
allergens (Amb a
1) or peptides (Fel
d 1 and PLA A2)
associated with an
adjuvant (e.g.,
CaPO4, alum or
MPL)
AHR: Airway hyper-responsiveness; BAL: Bronchoalveolar lavage; HDM: House dust mite; MPL:
Monophosphoryl lipid A; OVA: Ovalbumin; PGD2: Prostaglandin D2; PLA A2: Phospholipase A2.
For instance, a comparative clinical trial conducted in 165 grass pollen-allergic patients has shown that
ILIT is comparable to SCIT in terms of its efficacy, even when very low doses of allergens are used. [22] In
this study, patients were randomized to receive either SCIT with pollen extracts for over 3 years (with
cumulative allergen doses corresponding to 4 million standardized quality units) or ILIT consisting of three
intralymphatic injections for over 2 months (with corresponding cumulative allergen doses of 3000
standardized quality units). In this setting, ILIT improved hayfever symptoms, reduced skin prick test
reactivity while enhancing patient quality-of-life and compliance. In terms of safety, ILIT exhibited only
mild side effects in the form of local pain or inflammation.
Overall, ILIT has provided promising clinical results and, as such, represents an attractive new approach,
potentially reducing treatment duration from years to weeks. However, additional developments are
necessary, including the need to assess efficacy and to optimize treatment dose in large Phase III studies. In
addition, the use of complex medical equipment associated with the training of skilled personnel may also
hinder its broad use in humans.
Tolerance Induction by Skin & Mucosal Routes of Administration
Clinical Trials With Epicutaneous Allergen-specific Immunotherapy
Epicutaneous (skin application) allergen-specific immunotherapy (EPIT) is growing in interest, as it
represents a safe, noninvasive and patient friendly treatment for IgE-mediated allergic diseases linked with
either respiratory or food allergens ( Table 1 ). More than 50 years ago, pioneer studies demonstrated
clinical efficacy following EPIT in grass pollen-allergic patients. However, the use of skin scarification was
quite burdensome precluding its broad use in humans.[23–25] Currently, novel approaches have been
developed to increase the safety and efficacy of EPIT. In particular, a recent study by Senti et al. reports the
results from a Phase I/II study documenting the safety and efficacy of EPIT in patients allergic to grass
pollen allergens (i.e., Phleum pratense extract).[26] Allergic symptoms were reduced in nasal provocation
tests, even if the efficacy was not significantly higher in the active group when compared with the placebo.
No serious adverse events were recorded except for local eczematous reactions, probably due to the tapestripping of the skin before EPIT, which may induce the release of proinflammatory cytokines (i.e., IL-1,
IL-6, IL-8 or TNF-α) by keratinocytes.
Table 1. Comparative properties of parenteral routes of allergen immunotherapy.
Route
Allergens
Clinical efficacy
Immune mechanisms
Ref.
Epicutaneous
Grass pollens,
HDM and food
allergens (cow's
milk, egg and
peanut)
Used as natural
extracts onto intact
or tape-stripped
skin
Amelioration in nasal
symptoms (grass
pollen)
Well tolerated with
minor local eczematous
reactions (grass pollen
and cow's milk)
Need for efficacy
studies in humans
No immunological
change in humans
Decrease in AHR,
eosinophils in BAL and
Th2 responses in mice
(OVA, grass pollen,
HDM and peanut)
[23–
27,85,86,105]
Excellent efficacy to
reduce asthma and
rhinoconjonctivitis
symptoms, as well as
drug consumption in
patients allergic to
HDM, pollen (grass
and tree), insect venom
and cat dander
Need for medical
supervision and risk of
anaphylaxis
Products prepared for a
patient on the basis of
the physician's
prescription – so-called
named-patient products
Decrease in
inflammatory mediators
(i.e., histamine, N-αtosyl L-arginine methyl
ester esterase, kinins,
PGD2 and
myeloperoxydase) and
migration of mast cells,
eosinophils and
basophils within target
organs (skin, nose and
lung)
Increase in seric IgG4s
(blocking antibodies)
Increase, then
progressive decline of
seric IgEs
Decrease in Th2
responses and induction
of Th1s and Tregs (both
[11–
17,117,118,125–
131,133,134]
Pollens (grasses,
ragweed, birch,
Parietaria and
olive), HDM, cat
dander and
venoms
Used as natural
biological extracts,
allergoids,
recombinant
Subcutaneous
proteins (Bet v 1,
Phlp-1, -2, -5 and 6), purified natural
allergens (Amb a
1) or peptides (Fel
d 1 and PLA A2)
associated with an
adjuvant (e.g.,
CaPO4, alum or
MPL)
systemic and local)
AHR: Airway hyper-responsiveness; BAL: Bronchoalveolar lavage; HDM: House dust mite; MPL:
Monophosphoryl lipid A; OVA: Ovalbumin; PGD2: Prostaglandin D2; PLA A2: Phospholipase A2.
A new epicutaneous delivery systems (i.e., Viaskin®, DBV technology, Bagneux, France) is currently been
tested in humans. It consists of a condensation chamber that allows the release of soluble allergens while
hydrating layers of the epidermis. The evaluation of this delivery system in children allergic to cow's milk
in a pilot EPIT study confirmed that the treatment was well tolerated. However, neither clinical efficacy nor
immunological changes (i.e., a decrease in cow's milk-specific IgEs) were documented in this study.[27]
Taken together, those studies suggest that the EPIT approach is safe and well tolerated, and paves the way
for further investigations into its efficacy for the treatment of respiratory or food allergies in large cohorts
of patients. Further developments should take into account the allergen dose, as well as the number and
duration of allergen administrations.
Clinical Trials With Intranasal Allergen-specific Immunotherapy
Local nasal immunotherapy (LNIT) consists of spraying allergen extracts into the nasal cavity. It was first
investigated at the end of the 1970s, with encouraging clinical data ( Table 2 ). LNIT is performed by the
administration of natural biological or chemically-modified (allergoid, preventing IgE reactivity) allergen
extracts in a soluble form. It demonstrates a significant reduction in both symptoms and medication needed
in patients allergic to ragweed and grass pollens.[28–31] Adverse effects are mainly limited to the site of
administration.[30,32] Subsequent intranasal vaccines based on allergen extracts in macronized powder forms
(e.g., Parietaria, birch and grass) or on allergen-coated strips (e.g., mites) enhance clinical efficacy, while
decreasing local adverse effects in allergic patients.[32–38] Long-lasting effects of LNIT induced by a 4-year
treatment are noticed on nasal symptoms.[39,40] Recently, LNIT with rBet v 1 reduced nasal flow in birch
pollen-allergic patients.[41] Interestingly, the use of hypoallergenic rBet v 1 fragments had no effect on
symptom scores, suggesting that the presence of IgE epitopes is mandatory in allergen-specific tolerance
induction.[41]
Table 2. Comparative properties of skin and mucosal routes of allergen
immunotherapy.
Route
Allergens
Grass pollens,
HDM and
food allergens
(cow's milk,
egg and
Epicutaneous peanut)
Used as
natural
extracts onto
intact or tapestripped skin
Nasal
Pollens
(grasses,
Clinical
efficacy
Immune mechanisms
Ref.
Amelioration in
nasal symptoms
(grass pollen)
Well tolerated
with minor local
eczematous
reactions (grass
pollen and cow's
milk)
Need for
efficacy studies
in humans
No immunological
change in humans
Decrease in AHR,
eosinophils in BAL and
Th2 responses in mice
(OVA, grass pollen,
HDM and peanut)
[23–27,85,86,105]
Improvement of
clinical efficacy
Reduction of
inflammatory infiltration
[28–41,87,91,95,97,98,102–
ragweed,
Parietaria
and birch) and
HDM
Used as
natural
extracts,
allergoids,
macronized
powder forms
and strips
coated with
extracts
and long-lasting
protective
effects in
patients with
rhinitis (grass,
birch, ragweed,
Parietaria
pollens and
HDM)
Local reaction
and complex
administration
Need of largescale clinical
studies
and ICAM-1 expression
at local site (Parietaria)
Rise in IgAs, IgEs and
IgGs (ragweed and
grass)
Reduction of AHR,
eosinophils in BALs,
Th2 responses and seric
IgEs but induction of
Th1 cells/Tregs and
IgAs in saliva from
murine models
104]
Oral
Pollens
(grasses,
ragweed,
Artemisia and
birch), HDM
and food
allergens
(cow's milk,
egg and
peanut)
Used as
natural extract
in aqueous,
freeze-dried
and powder
forms and
enterosoluble
capsules
Reduction of
asthma/rhinitis
symptoms both
in adults and
children allergic
to HDM and
pollen (birch
and ragweed)
Improvement in
food (cow's
milk, egg and
peanut) intake
Risk of
anaphylaxis
Lack of a
control group
and studies with
a large cohort of
patients
Increased in IgG4s
(birch, cow's milk, egg
and peanut) whereas
IgEs are not altered
Decrease of Th2
responses in children
outgrowing their allergy
Induction of
FoxP3hiCD4+CD25+ T
cells in children (peanut)
and various Tregs (e.g.,
Th3, type 1 Tregs,
LAP+TGF-β+ and IL10+FoxP3+CD4+CD25+
T cells) in murine
models
Sublingual
Pollens
(grasses,
ragweed,
Parietaria,
birch and
olive) and
HDM
Used as
natural
biological
extracts,
allergoids and
recombinant
proteins (Bet
v 1) in soluble
form or
tablets
Very efficient in
treating type I
allergies in
either HDM or
pollens (from
grass,
Parietaria,
olive, ragweed
and Cupressus)
on symptoms
and medication
requirements
both in adults
and children
Diseasemodifying effect
after 3 years of
treatments
Excellent safety
Decrease in recruitment
of mast cells, eosinophils
and basophils
Increase, then
progressive decline of
seric IgEs, whereas seric
IgG4s (blocking
antibodies) and in
mucosal IgAs increase
[2,3,5–
Decrease in Th2
10,63,69,79,84,114,123,148]
responses while
promoting Th1 and
Tregs (both systemic and
local)
Tolerogenic Langerhans
cells and macrophages
driving suppressive
Th1/Treg responses in
the sublingual mucosa
[42–59,107,113,117]
profile with only Few proinflammatory
local adverse
cells (i.e., mast cells) in
events (i.e., oral submucosal tissues
pruritus, throat
irritation or
tongue swelling)
SLIT is
recommended
by the WAO and
the ARIA group
Named-patient
products and
marketing
authorization for
tablets
AHR: Airway hyper-responsiveness; ARIA: Allergic Rhinitis and its Impact on Asthma; BAL:
Bronchoalveolar lavage; HDM: House dust mite; OVA: Ovalbumin; SLIT: Sublingual immunotherapy;
WAO: World Allergy Organization.
Altogether, LNIT appears to be of interest in the treatment of allergic rhinitis patients, since it is safe and
efficient. However, better compliance is needed due to frequent nasal reactions. Also, it remains difficult to
control the exact dose of allergen administered when using this route. DBPC Phase III studies are required
to further document its safety and efficacy prior to a wide use in humans.
Clinical Trials With Oral Allergen-specific Immunotherapy
The use of oral allergen-specific immunotherapy (OIT) started 30 years ago, in patients with polleninduced allergic rhinitis ( Table 2 ).[42–50] Although well tolerated, OIT with grass pollen extracts (low and
high doses) as an aqueous solution, a powder or enterosoluble forms, is clinically and immunologically
ineffective in adults.[42–45] Alternatively, OIT with high doses of aqueous extracts (i.e., Dermatophagoides
pteronyssinus or Artemisia)[49,51] or using encapsulated allergens (i.e., birch or ragweed)[46–48,50] is shown to
be safe and efficient in both adults and children.
Table 2. Comparative properties of skin and mucosal routes of allergen
immunotherapy.
Route
Allergens
Grass pollens,
HDM and
food allergens
(cow's milk,
egg and
Epicutaneous peanut)
Used as
natural
extracts onto
intact or tapestripped skin
Clinical
efficacy
Immune mechanisms
Ref.
Amelioration in
nasal symptoms
(grass pollen)
Well tolerated
with minor local
eczematous
reactions (grass
pollen and cow's
milk)
Need for
efficacy studies
in humans
No immunological
change in humans
Decrease in AHR,
eosinophils in BAL and
Th2 responses in mice
(OVA, grass pollen,
HDM and peanut)
[23–27,85,86,105]
Nasal
Pollens
(grasses,
ragweed,
Parietaria
and birch) and
HDM
Used as
natural
extracts,
allergoids,
macronized
powder forms
and strips
coated with
extracts
Improvement of
clinical efficacy
and long-lasting
protective
effects in
patients with
rhinitis (grass,
birch, ragweed,
Parietaria
pollens and
HDM)
Local reaction
and complex
administration
Need of largescale clinical
studies
Reduction of
inflammatory infiltration
and ICAM-1 expression
at local site (Parietaria)
Rise in IgAs, IgEs and
IgGs (ragweed and
grass)
Reduction of AHR,
eosinophils in BALs,
Th2 responses and seric
IgEs but induction of
Th1 cells/Tregs and
IgAs in saliva from
murine models
Oral
Pollens
(grasses,
ragweed,
Artemisia and
birch), HDM
and food
allergens
(cow's milk,
egg and
peanut)
Used as
natural extract
in aqueous,
freeze-dried
and powder
forms and
enterosoluble
capsules
Reduction of
asthma/rhinitis
symptoms both
in adults and
children allergic
to HDM and
pollen (birch
and ragweed)
Improvement in
food (cow's
milk, egg and
peanut) intake
Risk of
anaphylaxis
Lack of a
control group
and studies with
a large cohort of
patients
Increased in IgG4s
(birch, cow's milk, egg
and peanut) whereas
IgEs are not altered
Decrease of Th2
responses in children
outgrowing their allergy
Induction of
FoxP3hiCD4+CD25+ T
cells in children (peanut)
and various Tregs (e.g.,
Th3, type 1 Tregs,
LAP+TGF-β+ and IL10+FoxP3+CD4+CD25+
T cells) in murine
models
Sublingual
Pollens
(grasses,
ragweed,
Parietaria,
birch and
olive) and
HDM
Used as
natural
biological
extracts,
allergoids and
recombinant
proteins (Bet
v 1) in soluble
form or
tablets
Very efficient in
treating type I
allergies in
either HDM or
pollens (from
grass,
Parietaria,
olive, ragweed
and Cupressus)
on symptoms
and medication
requirements
both in adults
and children
Diseasemodifying effect
after 3 years of
Decrease in recruitment
of mast cells, eosinophils
and basophils
Increase, then
progressive decline of
seric IgEs, whereas seric
IgG4s (blocking
antibodies) and in
[2,3,5–
mucosal IgAs increase
10,63,69,79,84,114,123,148]
Decrease in Th2
responses while
promoting Th1 and
Tregs (both systemic and
local)
Tolerogenic Langerhans
cells and macrophages
driving suppressive
[28–41,87,91,95,97,98,102–
104]
[42–59,107,113,117]
treatments
Excellent safety
profile with only
local adverse
events (i.e., oral
pruritus, throat
irritation or
tongue swelling)
SLIT is
recommended
by the WAO and
the ARIA group
Named-patient
products and
marketing
authorization for
tablets
Th1/Treg responses in
the sublingual mucosa
Few proinflammatory
cells (i.e., mast cells) in
submucosal tissues
AHR: Airway hyper-responsiveness; ARIA: Allergic Rhinitis and its Impact on Asthma; BAL:
Bronchoalveolar lavage; HDM: House dust mite; OVA: Ovalbumin; SLIT: Sublingual immunotherapy;
WAO: World Allergy Organization.
Today, OIT is mainly applied as a treatment for adults and children with food allergies, including cow's
milk, egg, peanuts, tree nuts, wheat, soy, fish and shellfish allergies. Most children with cow's milk and egg
allergies generally outgrow their disease in the first 6 years of life, whereas peanut, tree nut, fish or
shellfish allergies are permanent and the reactions are often more severe. Owing to the risk of adverse
effects, OIT requires the administration of small amounts of allergen (from micrograms to milligrams) by
the oral route in order to re-establish a long-lasting tolerance to dietary proteins.[52] To monitor OIT
efficacy, a food challenge is usually performed at the end of the study protocol. Many studies performed in
children with allergies to egg[53] or cow's milk[54–57] showed clinical efficacy results, as well as a good
safety profile. Also, long-lasting effects were observed for up to 4–5 years after the end of treatment.[55]
Nevertheless, some difficulties are faced in evaluating OIT efficacy in those studies since they often rely
upon small cohorts of patients and have to take into account spontaneous recovery rates. Overcoming such
limitations, a recent study that included children with a severe and lifelong allergy to cow's milk (i.e., cow's
milk specific IgEs >85 kU/l) revealed a significant improvement in tolerated food allergen intake.
Specifically, 36% of children became fully tolerant and 54% were able to drink limited amounts of cow's
milk. Interestingly, the control group maintained on a cow's milk-free diet failed the food challenge after 1
year.[57] In addition, Skripak et al. performed the first DBPC study of OIT that confirmed the safety and
efficacy of OIT in cow's milk allergy.[58] Specifically, patients in the active group exhibited a significant
increase in their tolerization threshold when compared with the placebo group, with a median cumulative
dose of 5140 and 40 mg of allergen tolerated, respectively. Those observations were extended to peanut
OIT, as demonstrated in a DBPC study providing evidence for a successful oral food challenge in the active
group associated with reduced skin prick tests.[59]
Altogether, OIT has shown encouraging clinical data, especially in patients with food allergies. However,
many questions remain unaddressed, such as the risks linked with OIT compared with eviction, dose
incrementation and patient selection, as well as low allergen/protein bioavailability to the gut due to gastric
enzymatic degradation. Further studies with large patients groups are necessary in order to address these
concerns and firmly establish the clinical efficacy of OIT in humans.
Clinical Trials With Sublingual Allergen-specific Immunotherapy
Allergen-specific SLIT was introduced in 1970 for respiratory allergies [60] and shown to improve symptoms
in allergic patients, although the optimal dose, the efficacy and associated mechanisms were not well
documented until the early 2000s ( Table 2 ).[61–68] Today, many DBPC studies, as well as meta-analyses,
have shown that SLIT is effective in decreasing both immediate- and late-phase symptoms, as well as the
need for medication, in adult and pediatric patients with allergic rhinoconjunctivitis to either pollens (from
common grasses, ragweed, Parietaria, birch, olive and Cupressus), HDM or cat dander.[63,69–76] SLIT
consists into the administration of high doses of natural-allergen extracts (pollens, mites or animal dander)
as drops or tablets under the tongue, prior to swallowing. Generally, SLIT is administered once-daily for a
period of time (e.g., 1–3 years). An excellent safety profile is recorded in SLIT studies, with more than 2
billion doses administered to either adults or children. [63,69,77,78] Only moderate adverse events occur locally
at the start of the treatment, including oral pruritus, throat irritation or tongue swelling, but severe systemic
reactions are extremely rare.
Table 2. Comparative properties of skin and mucosal routes of allergen
immunotherapy.
Clinical
efficacy
Immune mechanisms
Ref.
Grass pollens,
HDM and
food allergens
(cow's milk,
egg and
Epicutaneous peanut)
Used as
natural
extracts onto
intact or tapestripped skin
Amelioration in
nasal symptoms
(grass pollen)
Well tolerated
with minor local
eczematous
reactions (grass
pollen and cow's
milk)
Need for
efficacy studies
in humans
No immunological
change in humans
Decrease in AHR,
eosinophils in BAL and
Th2 responses in mice
(OVA, grass pollen,
HDM and peanut)
[23–27,85,86,105]
Nasal
Pollens
(grasses,
ragweed,
Parietaria
and birch) and
HDM
Used as
natural
extracts,
allergoids,
macronized
powder forms
and strips
coated with
extracts
Improvement of
clinical efficacy
and long-lasting
protective
effects in
patients with
rhinitis (grass,
birch, ragweed,
Parietaria
pollens and
HDM)
Local reaction
and complex
administration
Need of largescale clinical
studies
Reduction of
inflammatory infiltration
and ICAM-1 expression
at local site (Parietaria)
Rise in IgAs, IgEs and
IgGs (ragweed and
grass)
Reduction of AHR,
eosinophils in BALs,
Th2 responses and seric
IgEs but induction of
Th1 cells/Tregs and
IgAs in saliva from
murine models
Oral
Pollens
(grasses,
ragweed,
Artemisia and
birch), HDM
and food
allergens
Reduction of
asthma/rhinitis
symptoms both
in adults and
children allergic
to HDM and
pollen (birch
Increased in IgG4s
(birch, cow's milk, egg
and peanut) whereas
IgEs are not altered
Decrease of Th2
responses in children
outgrowing their allergy
Route
Allergens
[28–41,87,91,95,97,98,102–
104]
[42–59,107,113,117]
(cow's milk,
egg and
peanut)
Used as
natural extract
in aqueous,
freeze-dried
and powder
forms and
enterosoluble
capsules
Sublingual
and ragweed)
Improvement in
food (cow's
milk, egg and
peanut) intake
Risk of
anaphylaxis
Lack of a
control group
and studies with
a large cohort of
patients
Very efficient in
treating type I
allergies in
either HDM or
pollens (from
grass,
Parietaria,
olive, ragweed
and Cupressus)
Pollens
on symptoms
(grasses,
and medication
ragweed,
requirements
Parietaria,
both in adults
birch and
and children
olive) and
DiseaseHDM
modifying effect
Used as
after 3 years of
natural
treatments
biological
Excellent safety
extracts,
profile with only
allergoids and
local adverse
recombinant
events (i.e., oral
proteins (Bet
pruritus, throat
v 1) in soluble
irritation or
form or
tongue swelling)
tablets
SLIT is
recommended
by the WAO and
the ARIA group
Named-patient
products and
marketing
authorization for
tablets
Induction of
FoxP3hiCD4+CD25+ T
cells in children (peanut)
and various Tregs (e.g.,
Th3, type 1 Tregs,
LAP+TGF-β+ and IL10+FoxP3+CD4+CD25+
T cells) in murine
models
Decrease in recruitment
of mast cells, eosinophils
and basophils
Increase, then
progressive decline of
seric IgEs, whereas seric
IgG4s (blocking
antibodies) and in
mucosal IgAs increase
Decrease in Th2
responses while
[2,3,5–
promoting Th1 and
10,63,69,79,84,114,123,148]
Tregs (both systemic and
local)
Tolerogenic Langerhans
cells and macrophages
driving suppressive
Th1/Treg responses in
the sublingual mucosa
Few proinflammatory
cells (i.e., mast cells) in
submucosal tissues
AHR: Airway hyper-responsiveness; ARIA: Allergic Rhinitis and its Impact on Asthma; BAL:
Bronchoalveolar lavage; HDM: House dust mite; OVA: Ovalbumin; SLIT: Sublingual immunotherapy;
WAO: World Allergy Organization.
To date, the pertinence of SLIT for tolerance induction in humans has been confirmed by multiple DBPC
studies conducted in large cohorts of patients allergic to grass pollen. [3,5–10,79] Also, long-term clinical
benefits of SLIT have been documented following a 3-year treatment with two different grass allergy
immunotherapy tablets in adults with rhinitis, demonstrating clinical improvements sustained for at least 2
years after stopping the treatment (i.e., a 'disease-modifying' effect of SLIT).
Those observations are not restricted to grass pollen allergy. HDM sublingual tablets (with both D.
pteronyssinus and Dermatophagoides farinae mite species) tested in 509 adult patients in a pivotal Phase
IIb/III clinical trial, also induced a significant decrease in rhinitis symptoms, while demonstrating an
excellent safety profile after only 1 year of treatment, with sustained clinical benefit during the second
treatment-free year [Bergmann KC et al., Unpublished Data]. The efficacy and safety of SLIT using HDM
extracts as a solution were also demonstrated in adult patients suffering from mild to moderate asthma in a
Phase III, DBPC study (conducted in 484 adults), thus strengthening the pertinence of SLIT to promote
allergen-specific tolerance in humans suffering from rhinitis to mild–moderate asthma [Bergmann KC et
al., Unpublished Data]. Beyond respiratory diseases, encouraging preliminary data suggests that SLIT (and
also SCIT) with HDM allergens may provide benefit to patients with atopic dermatitis, based upon severity
symptom score (scoring atopic dermatitis) as well as the use of symptomatic medications. [80–82]
Collectively, these data compiled in a recent review show that SLIT efficacy is comparable to SCIT. [83]
However, one of the advantages of SLIT is that it is safer than SCIT, with a significantly lower risk of
inducing systemic reactions. Noticeably, the use of SLIT is recommended in position papers by the World
Allergy Organization (WAO) and by the Allergic Rhinitis and its Impact on Asthma (ARIA) group. [2,84]
Mechanisms of Action of T Lymphocytes
Successful AIT is often associated with humoral and cellular immune changes both in serum and at the
local site ( Table 1 & Table 2 & Figure 1). Regarding the intralymphatic and epicutaneous routes,
mechanisms in humans are currently under investigation. However, SCIT and SLIT mechanisms have been
particularly well documented and we have now converging arguments pinpointing key biological changes.
Preclinical models were also useful in characterizing immune mechanisms involved during AIT, by both
parenteral and mucosal routes.
Table 1. Comparative properties of parenteral routes of allergen immunotherapy.
Route
Allergens
Clinical efficacy
Immune mechanisms
Ref.
Epicutaneous
Grass pollens,
HDM and food
allergens (cow's
milk, egg and
peanut)
Used as natural
extracts onto intact
or tape-stripped
skin
Amelioration in nasal
symptoms (grass
pollen)
Well tolerated with
minor local eczematous
reactions (grass pollen
and cow's milk)
Need for efficacy
studies in humans
No immunological
change in humans
Decrease in AHR,
eosinophils in BAL and
Th2 responses in mice
(OVA, grass pollen,
HDM and peanut)
[23–
27,85,86,105]
Pollens (grasses,
ragweed, birch,
Parietaria and
olive), HDM, cat
dander and
Subcutaneous venoms
Used as natural
biological extracts,
allergoids,
recombinant
proteins (Bet v 1,
Excellent efficacy to
reduce asthma and
rhinoconjonctivitis
symptoms, as well as
drug consumption in
patients allergic to
HDM, pollen (grass
and tree), insect venom
and cat dander
Need for medical
supervision and risk of
Decrease in
inflammatory mediators
(i.e., histamine, N-αtosyl L-arginine methyl
ester esterase, kinins,
PGD2 and
myeloperoxydase) and
migration of mast cells,
eosinophils and
basophils within target
organs (skin, nose and
[11–
17,117,118,125–
131,133,134]
Phlp-1, -2, -5 and 6), purified natural
allergens (Amb a
1) or peptides (Fel
d 1 and PLA A2)
associated with an
adjuvant (e.g.,
CaPO4, alum or
MPL)
anaphylaxis
Products prepared for a
patient on the basis of
the physician's
prescription – so-called
named-patient products
lung)
Increase in seric IgG4s
(blocking antibodies)
Increase, then
progressive decline of
seric IgEs
Decrease in Th2
responses and induction
of Th1s and Tregs (both
systemic and local)
AHR: Airway hyper-responsiveness; BAL: Bronchoalveolar lavage; HDM: House dust mite; MPL:
Monophosphoryl lipid A; OVA: Ovalbumin; PGD2: Prostaglandin D2; PLA A2: Phospholipase A2.
Table 2. Comparative properties of skin and mucosal routes of allergen
immunotherapy.
Clinical
efficacy
Immune mechanisms
Ref.
Grass pollens,
HDM and
food allergens
(cow's milk,
egg and
Epicutaneous peanut)
Used as
natural
extracts onto
intact or tapestripped skin
Amelioration in
nasal symptoms
(grass pollen)
Well tolerated
with minor local
eczematous
reactions (grass
pollen and cow's
milk)
Need for
efficacy studies
in humans
No immunological
change in humans
Decrease in AHR,
eosinophils in BAL and
Th2 responses in mice
(OVA, grass pollen,
HDM and peanut)
[23–27,85,86,105]
Nasal
Pollens
(grasses,
ragweed,
Parietaria
and birch) and
HDM
Used as
natural
extracts,
allergoids,
macronized
powder forms
and strips
coated with
extracts
Improvement of
clinical efficacy
and long-lasting
protective
effects in
patients with
rhinitis (grass,
birch, ragweed,
Parietaria
pollens and
HDM)
Local reaction
and complex
administration
Need of largescale clinical
studies
Reduction of
inflammatory infiltration
and ICAM-1 expression
at local site (Parietaria)
Rise in IgAs, IgEs and
IgGs (ragweed and
grass)
Reduction of AHR,
eosinophils in BALs,
Th2 responses and seric
IgEs but induction of
Th1 cells/Tregs and
IgAs in saliva from
murine models
Oral
Pollens
(grasses,
ragweed,
Reduction of
asthma/rhinitis
symptoms both
Increased in IgG4s
(birch, cow's milk, egg
and peanut) whereas
Route
Allergens
[28–41,87,91,95,97,98,102–
104]
[42–59,107,113,117]
Artemisia and
birch), HDM
and food
allergens
(cow's milk,
egg and
peanut)
Used as
natural extract
in aqueous,
freeze-dried
and powder
forms and
enterosoluble
capsules
Sublingual
in adults and
children allergic
to HDM and
pollen (birch
and ragweed)
Improvement in
food (cow's
milk, egg and
peanut) intake
Risk of
anaphylaxis
Lack of a
control group
and studies with
a large cohort of
patients
Very efficient in
treating type I
allergies in
either HDM or
pollens (from
grass,
Parietaria,
olive, ragweed
and Cupressus)
Pollens
on symptoms
(grasses,
and medication
ragweed,
requirements
Parietaria,
both in adults
birch and
and children
olive) and
DiseaseHDM
modifying effect
Used as
after 3 years of
natural
treatments
biological
Excellent safety
extracts,
profile with only
allergoids and
local adverse
recombinant
events (i.e., oral
proteins (Bet
pruritus, throat
v 1) in soluble
irritation or
form or
tongue swelling)
tablets
SLIT is
recommended
by the WAO and
the ARIA group
Named-patient
products and
marketing
authorization for
tablets
IgEs are not altered
Decrease of Th2
responses in children
outgrowing their allergy
Induction of
FoxP3hiCD4+CD25+ T
cells in children (peanut)
and various Tregs (e.g.,
Th3, type 1 Tregs,
LAP+TGF-β+ and IL10+FoxP3+CD4+CD25+
T cells) in murine
models
Decrease in recruitment
of mast cells, eosinophils
and basophils
Increase, then
progressive decline of
seric IgEs, whereas seric
IgG4s (blocking
antibodies) and in
mucosal IgAs increase
Decrease in Th2
responses while
[2,3,5–
promoting Th1 and
10,63,69,79,84,114,123,148]
Tregs (both systemic and
local)
Tolerogenic Langerhans
cells and macrophages
driving suppressive
Th1/Treg responses in
the sublingual mucosa
Few proinflammatory
cells (i.e., mast cells) in
submucosal tissues
AHR: Airway hyper-responsiveness; ARIA: Allergic Rhinitis and its Impact on Asthma; BAL:
Bronchoalveolar lavage; HDM: House dust mite; OVA: Ovalbumin; SLIT: Sublingual immunotherapy;
WAO: World Allergy Organization.
Figure 1. Impact of allergen immunotherapy on local and systemic immunological mechanisms.
Allergen immunotherapy alters both humoral and cellular allergen-specific responses. The Th1:Th2 ratio is
increased and Tregs are induced at both local and systemic levels. IL-10 is increased by monocytes,
dendritic cells, T lymphocytes and B lymphocytes. Both mucosal (i.e., IgA) and seric (IgG1 and IgG4)
blocking antibodies inhibit the binding of allergen–IgE complexes to proinflammatory cells (e.g., mast
cells). Proinflammatory mediators as well as the migration of mast cells are decreased within target organs
(i.e., skin, nose and lung).
AIT: Allergen immunotherapy.
Immune Changes in Preclinical Models
Preclinical models of established asthma using aero- (i.e., ovalbumin, pollen and HDM) or food allergens
(peanut) have been developed to decipher immune mechanisms underlying AIT efficacy using allergen
extracts,[85–87] purified/recombinant allergens (e.g., ovalbumin, Bet v 1, Der p 1 and Der p 2) [88–97] or
polypeptide fragments (e.g., Bet v 1, Phl p 1 and Phl p 5) [98] alone, or with an adjuvant (e.g., Toll-like
receptor agonists, probiotics or immunomodulatory proteins) [89,91–93,95–97] or a vector system (e.g.,
condensation chamber [Viaskin], genetically detoxified bacterial products or nano-/microparticles).[85,86,88,90,94,99–101] In those models, tolerance induction was achieved either by the
epicutaneous,[85,86] sublingual[88–90,92–94,96,100,101] or nasal[87,91,97,98,102–104] routes, in association with a
reduction of both airway hyper-responsiveness, eosinophils in bronchoalveolar lavages as well as allergenspecific Th2 cell responses (i.e., IL-5 and IL-13) and an induction of Th1 (i.e., IFN-γ) and Tregs. The nasal,
sublingual and epicutaneous routes were shown to promote mainly the development of FoxP3 +/IL-10producing T cells,[88,98,104–106] whereas allergen exposure to the oral or gut mucosae rather generated the
expansion of more diverse Tregs (i.e., FoxP3+, CTLA4+, PD-L1+, TGF-β+, IL-10+, LAP+TGF-β+ and TGFβ+IL-10+).[107–112] Noticeably, a new mechanism of oral tolerance induction, recently described, involves
FoxP3+ Tregs generated in the gut-draining lymph nodes, subsequently migrating into the gut to undergo
local expansion driven by IL-10-producing tolerogenic intestinal macrophages.[113] Lastly, AIT efficacy is
also related to humoral changes with a decrease in allergen-specific IgEs in serum.[85,86,103,104] However,
only the administration of allergens by mucosal routes is able to promote allergen-specific IgAs both in
serum and mucosal secretions.[94,97,102,104]
Immune Changes in Clinical Trials
In terms of mechanisms, successful AIT (i.e., subcutaneous, sublingual and nasal) with pollen (grass or
Parietaria) or HDM extracts inhibits the increase of adhesion molecules (i.e., ICAM-1), thus preventing
the recruitment of inflammatory cells (i.e., mast cells, eosinophils, basophils and neutrophils) within
mucosae (skin, nose or lung) and the release of proinflammatory mediators (i.e., N-α-Tosyl L-arginine
methyl ester esterase, kinins, prostaglandin D2, myeloperoxydase, tryptase and seric eosinophil cationic
protein).[2,38–40]
Clinically efficient AIT (i.e., subcutaneous, sublingual, nasal and oral) with pollen (grass/tree) or HDM
extracts also alters humoral responses. After a rise, AIT induces a persistent decrease in seric allergenspecific IgEs, mostly found after 6 months to 1 year of immunotherapy. A rapid and concomitant increase
in seric allergen-specific IgGs (mostly high-affinity IgG1s and IgG4s) is often associated with AIT
efficacy.[2,28,30,41,46–48,50,114,115] Similarly, OIT with food allergen extracts augments food (cow's milk, egg
and peanut)-specific IgG4s,[53,57,58,116] whereas food-specific IgEs do not change significantly in
most[53,57,58,116] but not all studies.[55,116] A 'blocking' role of IgG4s[2,117,118] appears to be linked with an
inhibition of the binding of allergen–IgE complexes to inflammatory cells, thus preventing histamine
release by basophils and antigen presentation to T cells.[119–122] When compared with parenteral routes,
mucosal administration (i.e., sublingual and nasal) enhances allergen-specific IgAs, both in serum and
mucosal secretions.[123,124]
The impact of AIT on cellular responses is particularly well documented in SCIT and SLIT. SCIT reorients
allergen-specific CD4+ T-cell responses in atopic patients from a Th2 (i.e., IL-4, IL-5 and IL-13)[125,126] to a
Th1 (i.e., IL-12/IFN-γ)[127–131] pattern in peripheral blood, but also within the target organs (the nasal
mucosa or the skin). In addition, both SCIT and SLIT have been shown to elicit Tregs in the blood,
belonging either to the type 1 Treg (i.e., IL-10), Th3 (i.e., TGF-β) or FoxP3+CD4+CD25+ T-cell subsets.[132–
134]
Those observations were confirmed by OIT studies since food allergen (cow's milk or egg)-specific Th2
responses decrease mainly in the case of spontaneous recovery. [52,56,116] In the latter situation, children
reorient their immune responses toward the Th1/Treg type,[52] similar to those undergoing successful peanut
OIT, whose increased FoxP3hiCD4+CD25+ T cells in the blood.[59] Furthermore, suppressive T cells seem to
play a crucial role at the administration site. Particularly, SLIT to grass pollen extracts was recently
demonstrated to be associated with the induction of FoxP3 + T cells in the sublingual mucosa.[123] The effect
of AIT on innate immune responses remains to be fully investigated. Nonetheless, a recent study suggests a
key role of PD-L1 expressed by APCs in the blood as a surrogate marker of SLIT efficacy in patients
allergic to ragweed.[135]
Focus on the Peculiar Biology of Sublingual Immunity
A detailed characterization of the sublingual immunity highlights the role of the sublingual mucosa as a
privileged site for AIT,[136] particularly owing to the atypical organization of the mucosal immune system.
As within the skin, Langerhans cells have been detected in the mucosa as key APCs with a strong capacity
to capture the allergen in vitro.[137,138] They express the high affinity receptor for IgE (FcεRI) as well as
Toll-like receptor 4, which triggers the induction of regulatory molecules (i.e., indoleamine 2,3dioxygenase, TGF-β and IL-10) and supports the development of IFN-γ/IL-10-producing CD4+ T cells.[139]
A detailed characterization of oral APCs in murine (i.e., BALB/c) mice also confirms the presence of
Langerhans cells in the mucosa itself but further reveals the presence of myeloid and plasmacytoid APCs in
submucosal tissues.[106] Particularly, tolerogenic macrophage-like cells expressing the β-integrin CD11b are
detected in the lamina propria and are found to capture and transport the allergen from the mucosa to
draining lymph nodes, thereby subsequently promoting the development of IL-10/IFN-γ-producing
suppressive CD4+ T cells in vivo.[88] A critical role for such sublingual macrophage-like cells in tolerance
induction during SLIT has been established by conditional ablation experiments in mice. Interestingly,
those cells are detected in the human oral mucosa [Bergmann KC et al., Unpublished Data]. Lastly, another
advantage of SLIT is that the sublingual mucosa has few proinflammatory cells such as mast cells and
eosinophils,[140–142] thus, making an allergic reaction less severe than when compared with systemic routes.
Future Perspective
To date, commercially available allergy vaccines are entirely based on natural- or modified-allergen
extracts. However, over the past 10 years, considerable attention has been given to the use of recombinant
allergens (i.e., in native or hypoallergenic forms) for AIT. [143] Most recombinant allergens take advantage
to be synthesized in large amounts and to be better characterized than natural extracts. Particularly,
recombinant allergens are of importance in the case of allergic patients sensitized to a limited number of
allergens (e.g., birch pollen allergy with more than 95% of patients exhibiting IgE reactivity to the Bet v 1
allergen).[144] The development of second-generation vaccines will also benefit from the use of adjuvant
(i.e., Toll-like receptor agonists, probiotics and immunomodulators)/delivery systems (i.e., detoxified
bacterial products and mucoadhesive particulate formulations) that target the allergen to tolerogenic
dendritic cells.[145] Monophosphoryl lipid A as well as CpG oligonucleotides are currently under
investigation for AIT in humans. Particularly, Phase I/IIa studies have shown encouraging clinical
outcomes that call for further investigations on large cohorts of patients. [146,147] Consequently, the use of
selected recombinant major allergens in association with appropriate adjuvant/vector systems will facilitate
the development of more efficient and safe allergy vaccines in the future.
Sidebar
Executive Summary






To date, the clinical efficacy of sublingual immunotherapy (SLIT) has been demonstrated in
allergic rhinitis (grass/tree pollen and house dust mites) in both adults and children, and further
evidence has been obtained in the management of mild-moderate asthma (house dust mite).
SLIT is now considered as the only established noninvasive alternative to subcutaneous
immunotherapy (SCIT).
Allergen immunotherapy products are only available for SCIT and SLIT on the basis of the
physician's prescription - so-called named-patient products or as SLIT tablets (with marketing
authorization).
SCIT and SLIT exhibit similar immune mechanisms (reduction of inflammatory cell recruitment,
induction of blocking allergen-specific IgG4s and immune deviation of CD4+ T cells from Th2 to
Th1 with the generation of suppressive cells [IL-10, TGF-β and FoxP3]), both systemically and
locally.
The oral mucosa is a privileged site of immune tolerance, explaining the superior safety of SLIT
when compared with SCIT (i.e., tolerogenic Langerhans cells such as IL-10, TGF-β and
indoleamine 2,3-dioxygenase) and lamina propria macrophages promotes the differentiation of
IFN-γ/IL-10 suppressive CD4+ T cells; proinflammatory cells (i.e., mast cells) are located deeper
in submucosal tissues, at a distance from the allergen administration.
Allergen immunotherapy evaluated via alternative routes (i.e., intralymphatic, epicutaneous,
intranasal and oral) to SCIT or SLIT has demonstrated promising preclinical and clinical data.
However, well-documented double-blind placebo-controlled Phase III studies in large cohorts of
patients are needed to further document safety and efficacy.
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Papers of special note have been highlighted as:
• of interest
•• of considerable interest
Immunotherapy. 2012;4(2):201-212. © 2012 Future Medicine Ltd.