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Sublingual immunotherapy for inhalant allergens Presented by Jaichat Mekaroonkamol, MD. May29, 2014
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Mechanism of Sublingual
Immunotherapy(SLIT)
For Inhalant Allergens
Jaichat Mekaroonkamol, MD.
SCIT SLIT
Safer
More convenient approach
MECHANISMS OF SUBLINGUAL IMMUNOTHERAPY: SLIT
• Langerhans cells, myeloid dendritic cells, and macrophages located in oral tissues, tonsils, and draining cervical lymph nodes are biased toward the induction of TH1 and IL-10 (producing CD4+ regulatory T cells)
Philippe Moingeon. J Allergy Clin Immunol: In Practice 2013;1:228-41
Mucosal tolerance
MECHANISMS OF SUBLINGUAL IMMUNOTHERAPY: SLIT
• Langerhans cells, myeloid dendritic cells, and macrophages located in oral tissues, tonsils, and draining cervical lymph nodes are biased toward the induction of TH1 and IL-10 (producing CD4+ regulatory T cells)
• Oral tissues contain limited numbers of mast cells located in submucosal areas, thereby explaining the well-established safety profile of SLIT, with mostly local but rare systemic reactions
Philippe Moingeon. J Allergy Clin Immunol: In Practice 2013;1:228-41
Philippe Moingeon. J Allergy Clin Immunol: In Practice 2013;1:228-41
Philippe Moingeon. J Allergy Clin Immunol: In Practice 2013;1:228-41
Few proinflammatory cell
3 subsets of dendritic cells
(DCs)
• Langerhans cells (LCs)
• oral epithelium
• Myeloid APCs (MDC)
• macrophage-like cells
• lamina propria
• Plasmacytoid DCs (pDCs) • subepithelial tissues
Middleton allergy 8th edition
• All DCs originate from a CD34+ precursor in the bone marrow
• Differentiate under the influence of hematopoietic cytokines
• Each type expressing specific markers
Helper T cell (Th) polarization by dendritic cells (DCs). Depending on • Type of antigen • Dose • Tissue environment where antigen is
first introduced
Oral mucosal dendritic cells
Jean-Pierre Allam and Natalija Novak. Current Opinion in Allergy and Clinical Immunology 2011, 11:571–578
Oral Langerhans cell
FcRI,CD23 High and Low
affinity IgE receptor
Efficient IgE mediated allergen capture
CD80,CD86 Binding to CTLA-4 >
CD28
Inhibitory signal
TLR4 Upregulate B7-H1,B7-H3
Development of Treg
Abbas. Cellular and Molecular Immunology 7th edition Peripheral: T-cell
“Anergy”
Lack of complete
signal for T cell
activation
Cytotoxic T lymphocytes
associated protein 4
• High affinity than CD 28 • Inhibitory receptor
Philippe Moingeon. J Allergy Clin Immunol: In Practice 2013;1:228-41
Few proinflammatory cell
• T lymphocytes are mostly located along the lamina propria, that is, in the vicinity of numerous APCs
• Include both regulatory as well as effector (TH1, TH2, or TH17) CD4+ T cells
• Altogether, TH1 and Treg cells differentiated from naive T cells in oral lymphoid organs are thought to be more critical than such resident CD4+ T cells for establishing SLIT-induced tolerance
Philippe Moingeon. J Allergy Clin Immunol: In Practice 2013;1:228-41
Few proinflammatory cell • MCs and Eos are found in
limited numbers in oral tissues
and are rather located in
subepithelial areas
• Oral mast cells (oMC) most
likely account for adverse
reactions such as oral itching
and sublingual edema caused
by histamine release
• Differences in relative
numbers of LCs and MCs have
been reported, depending on
the site considered
Allam et al. Allergy 2008: 63: 720–727
Allam et al. Allergy 2008: 63: 720–727
Allam et al. Allergy 2008: 63: 720–727
Mast cell: MC
Langerhans: LC
MCs appear to be closer to
the mucosal surface in
lingual tissues SLIT is
often associated with tongue
edemas
Allam et al. Allergy 2008: 63: 720–727
Human oral LCs were shown to efficiently capture allergens in
vitro. Such LCs express constitutively both low (CD23) and
high (FceRI) affinity receptors for IgE, likely contributing to IgEmediated allergen capture. Engagement of such FcR by allergen-IgE complexes
upregulates IL-10 and TGF-b secretion as well as indolamine-2-dioxygenase expression (a rate-limiting enzyme that metabolizes
tryptophan), thus revealing the tolerogenic phenotype of those cells
Philippe Moingeon. J Allergy Clin Immunol: In Practice 2013;1:228-41
The highest FcRI
expression could be
detected on oLC from the vestibulum
Allam et al. Allergy 2008: 63: 720–727
Macrophage: MC
Langerhans: LC
different mucosal regions
such as the vestibulum
might represent alternative
SLIT application sites with potent allergen uptake
Philippe Moingeon. J Allergy Clin Immunol: In Practice 2013;1:228-41
Few proinflammatory cell
• Innate lymphoid cells
• Can directly sense bacterial components
and exhibit a strong capacity to produce
cytokines such as IL-2, IL-5, IL-13 and IL-22
• In the absence of danger signals, the
responses induced CD4+ Treg lymphocytes
with a suppressive function on effector T
lymphocytes
• Lingual tonsils: anatomically the most
important
PHARMACODYNAMICS OF SUBLINGUAL IMMUNIZATION
• Tissues under the tongue are highly vascularized, with blood vessels draining directly into the jugular vein
– small synthetic molecules (such as the vasodilator glyceryl trinitrate) with the goal to obtain a peak plasmatic release within 5 to 10 minutes
– larger molecules (such as peptides or glycoproteins) are not directly adsorbed into the blood after sublingual administration
Philippe Moingeon. J Allergy Clin Immunol: In Practice 2013;1:228-41
Philippe Moingeon. J Allergy Clin Immunol: In Practice 2013;1:228-41
Mice received ragweed pollen extract
• assessing the biodistribution of iodine-123-radiolabelled Purified Der p 2 and its monomeric allergoid
• 7 allergic volunteers
• Assess by gel chromatography
Marcello Bagnasco et al. Arch Allergy Immunol 2005;138:197–202
Marcello Bagnasco et al. Arch Allergy Immunol 2005;138:197–202
• Not differ between allergen and allergoid.
• Plasma radioactivity began to increase only after swallowing and peaked at 1–2 h.
• Both the allergen and the allergoid persisted in the mouth for several hours, and traces could be detectable up to 20 h
• Specimens of oral vestibular region
from patients intraoral surgery, only
clinically noninflamed tissue
• n= 90 ( atopic; n=40, non atopic;n= 49)
• Age 27.1 ± 12.8
Allam et al. J Allergy Clin Immunol 2010;126:638-45.
Allam et al. J Allergy Clin Immunol 2010;126:638-45.
The cell of oral mucosa that takeup antigen appear to be
kept in an immature state
neg pos pos neg
• Significant uptake required more than 5 minutes
• Dose-dependent binding of Phl p 5 to oLCs was
saturated at 100 mg/mL Phl p 5.
• Enhanced migratory capacity
• Decelerated maturation of oLCs.
Allam et al. J Allergy Clin Immunol 2010;126:638-45.
Philippe Moingeon. J Allergy Clin Immunol: In Practice 2013;1:228-41
• allergens cross the mucosa within 15 to 30 minutes and are then captured and processed by APCs
• APCs migrate within 24 to 48 hours to draining cervical lymph nodes and tonsils
• CD4+ T-cell responses of the TH1 and Treg cell types are elicited within 2 to 5 days
Philippe Moingeon. J Allergy Clin Immunol: In Practice 2013;1:228-41
• allergens cross the mucosa within 15 to 30 minutes and are then captured and processed by APCs
• APCs migrate within 24 to 48 hours to draining cervical lymph nodes and tonsils
• CD4+ T-cell responses of the TH1 and Treg cell types are elicited within 2 to 5 days
• In patients with grass pollen allergy, the need for a 2- to 4-month pretreatment period before the pollen season
• Time needed to mount a robust Treg-cell response
Immune change induced by SLIT
Philippe Moingeon. J Allergy Clin Immunol: In Practice 2013;1:228-41
Middleton allergy 8th edition
Nerin N. Bahceciler et al. Int Arch Allergy Immunol 2005;136:287–294
• 31 asthma patients allergic to HDM were studied
received SLIT with a standardized Dp plus Df 50/50
extract
• groups I (n = 17): 6 months
• groups II (n = 14): 12 months
• A group of healthy children (n = 8) • Age 8.27 ± 2.87 years, female to male ratio = 18/13
Nerin N. Bahceciler et al. Int Arch Allergy Immunol 2005;136:287–294
P= 0.0001
P= 0.02
P= 0.0001
P= 0.01
P= 0.03
P= 0.003
Nerin N. Bahceciler et al. Int Arch Allergy Immunol 2005;136:287–294
P= 0.0001
P= 0.004 P= 0.002
P= 0.03
Nerin N. Bahceciler et al. Int Arch Allergy Immunol 2005;136:287–294
IgG4
IgE IgG1
IgA
• These data demonstrate that HDM-allergic asthma is characterized by increased allergen-specific IgE and IgG1 and decreased allergen-specific IgA responses.
• HDM-SLIT suppresses allergen-specific IgE and may have a stimulatory effect on allergen-specific IgA production.
Nerin N. Bahceciler et al. Int Arch Allergy Immunol 2005;136:287–294
P= 0.03
P= 0.003
These IgAs may act as powerful anti-inflammatory
antibodies, competing with IgEs for allergen binding, most
particularly because they are produced at the level of
mucosal surfaces. In this regard, the induction of such
secretory IgAs is expected to be significantly higher after
SLIT compared with SCIT
Philippe Moingeon. J Allergy Clin Immunol: In Practice 2013;1:228-41
Cristina Antfflnez et al. Pediatr Allergy Immunol 2008: 19: 210–218
• 23 children with respiratory disease monosensitized to Dermatophagoides pteronyssinus
• SLIT(n=12): glycerinated allergenic extract (SLIT® Tratamiento sublingual)
• SCIT(n=11): allergen extract adsorbed in aluminium hydroxide (Pangramin® Depot-UM)
• Over a 2-yr period
Cristina Antfflnez et al. Pediatr Allergy Immunol 2008: 19: 210–218
p < 0.05 p < 0.05
p < 0.005
p < 0.005
Cristina Antfflnez et al. Pediatr Allergy Immunol 2008: 19: 210–218
Cristina Antfflnez et al. Pediatr Allergy Immunol 2008: 19: 210–218
Cochrane Database review 2010
• Total of 60 RCTs
• SLIT reduction in AR compare with placebo
– Clinical score: SMD -0.49; 95%CI -0.64 to -0.34, P< 0.00001
– Medication requirement : SMD -0.32; 95%CI -0.43 to -0.21, P< 0.00001
• Smaller changes in specific IgE, specific IgG, and cytokines compared with SCIT
• Induction of allergen-specific IgG4 is a consistent finding in most SLIT studies using large doses of allergen
• Some studies reporting good clinical responses to SLIT have detected no change in allergen-specific IgE, IgG, or IgG4.
Cochrane Database Syst Rev 2010;(12): CD002893
Different immunologic response in
peripheral blood during treatment of SCIT and SLIT
Middleton allergy 8th edition
Philippe Moingeon. J Allergy Clin Immunol: In Practice 2013;1:228-41
Biomarkers for SLIT efficacy
Philippe Moingeon. J Allergy Clin Immunol: In Practice 2013;1:228-41
Short-term SLIT (hours to <1 wk)
Middleton allergy 8th edition
Desensitization
• A method of treating immediate hypersensitivity disease (allergies) that involves repetitive administration of low doses of an antigen to which individuals are allergic.
• This process often prevents severe allergic reactions on subsequent environmental exposure to the antigen, but the mechanisms are not well understood.
Abbas. Cellular and Molecular Immunology 7th edition
Philippe Moingeon. J Allergy Clin Immunol: In Practice 2013;1:228-41
Short-term SLIT (hours to <1 wk)
Philippe Moingeon. J Allergy Clin Immunol: In Practice 2013;1:228-41
Mid-term SLIT (1 wk to 6 mo)
Regulatory DC markers • C1Q
• Stabilin
• 89 eligible patients
• 1:1 to receive either a grass pollen or placebo
• 4 subgroups
– active responders (ARs; n = 21)
– active nonresponders (ANRs; n = 20)
– placebo responders (PRs; n = 7)
– placebo nonresponders (PNRs; n = 31)
• Whole blood was collected before and after 1 week and 1, 2, and 4 months of treatment
ZIMMER et al. J Allergy Clin Immunol 2012;129:1020-30
ZIMMER et al. J Allergy Clin Immunol 2012;129:1020-30
C1Q and STAB1 represent candidate biomarkers of
early efficacy of SLIT as the hallmark of a regulatory
innate immune response predictive of clinical tolerance.
Philippe Moingeon. J Allergy Clin Immunol: In Practice 2013;1:228-41
Long-term SLIT (6 mo to several yr)
FUTURE OF AIT
• not all patients will see improvement
• carries the risk of anaphylaxis
• number of administrations and the duration of the therapeutic course
A. Wesley Burks et al, J Allergy Clin Immunol 2013;131:1288-96.
Philippe Moingeon. J Allergy Clin Immunol: In Practice 2013;1:228-41
