allergy immunotherapy (mechanisms)
DESCRIPTION
Mechanisms of allergy immunotherapy Presented by Jaichat Mekaroonkamol, MD April24, 2014TRANSCRIPT
Allergy immunotherapy(AIT)
Mechanisms
Jaichat Mekaroonkamol, MD.
Immunotherapy for treating allergy
• Allergen-specific immunotherapy
• Specific immunotherapy
• Allergen immunotherapy
• Allergy immunotherapy (AIT)
immunotherapy can include both allergen specific and non specific approaches
• change the course of disease by altering the underlying natural history
• aim to induce immune tolerance to allergens esp. peripheral T cell tolerance
A. Wesley Burks et al, J Allergy Clin Immunol 2013;131:1288-96.
MECHANISMS OF ALLERGEN-SPECIFIC IMMUNOTHERAPY
A. Wesley Burks et al, J Allergy Clin Immunol 2013;131:1288-96.
Allergic inflammation
Nature Review, 2006
Immune Tolerance
Immune Tolerance
• Immature lymphocyte
• Negative selection
Central tolerance
• CD4+ T cell/ T helper cell
Peripheral tolerance
Abbas. Cellular and Molecular Immunology 7th edition
Abbas. Cellular and Molecular Immunology 7th edition
Central: Self-tolerance
• Clonal deletion
• Clonal anergy
T-cell: in thymus
• Self MHC
• Self antigen
• AIRE(autoimmune regulator)
B-cell: in BM
• Membrane IgM/B cell
Ig receptor
• Functional anergy
• Receptor editing
(light chain) Clonal
deletion
Abbas. Cellular and Molecular Immunology 7th edition
Central: T-cell
Abbas. Cellular and Molecular Immunology 7th edition
Central: B-cell
Abbas. Cellular and Molecular Immunology 7th edition Middleton allergy 8th edition
Peripheral: CD4+ T cell
• Anergy
• Suppression
• Deletion
B-cell
• T-dependent
• Anergy -> deletion
• Inhibitor reseptors
• T-independent
• Multivalent antigen
Immunological
privileged site
Abbas. Cellular and Molecular Immunology 7th edition Peripheral: T-cell
Abbas. Cellular and Molecular Immunology 7th edition Peripheral: T-cell
“Anergy”
Lack of complete
signal for T cell
activation
Abbas. Cellular and Molecular Immunology 7th edition
Abbas. Cellular and Molecular Immunology 7th edition
Inhibitory receptor CTLA-4
Abbas. Cellular and Molecular Immunology 7th edition Peripheral: T-cell
“Suppression”
Regulatory T cell
• Thymus
• Peripheral
lymphoid organs
Immature/ resting DC
Abbas. Cellular and Molecular Immunology 7th edition
The development and survival of these regulatory T cells require IL-2 and the
transcription factor FoxP3
Abbas. Cellular and Molecular Immunology 7th edition
Regulatory T-cell
Middleton allergy 8th edition
Treg cells directly or indirectly suppress all other effector T cell subsets
Middleton allergy 8th edition
Middleton allergy 8th edition
Abbas. Cellular and Molecular Immunology 7th edition Peripheral: T-cell
Abbas. Cellular and Molecular Immunology 7th edition Peripheral: T-cell
“Deletion”
T cells that recognize self antigens
in the absence of costimulation
may activate Bim, resulting in
apoptosis by the mitochondrial
pathway
Abbas. Cellular and Molecular Immunology 7th edition Peripheral: T-cell
“Deletion”
Repeated stimulation of T cells
results in the coexpression
of death receptors and their
ligands, and engagement
of the death receptors triggers
apoptotic death
Peripheral: CD4+ T cell
• Anergy
• Suppression
• Deletion
B-cell
• T-dependent
• Anergy -> deletion
• Inhibitor reseptors
• T-independent
• Multivalent antigen
Immunological
privileged site
Abbas. Cellular and Molecular Immunology 7th edition Middleton allergy 8th edition
Abbas. Cellular and Molecular Immunology 7th edition
Multiple mechanisms of immune tolerance
Middleton allergy 8th edition
MECHANISMS OF ALLERGEN-SPECIFIC IMMUNOTHERAPY
• Desensitization of FcRI
• T cell responses
• Allergen-specific IgE and IgG4 responses
• Regulation of mast cells, basophils, and eosinophils
A. Wesley Burks et al, J Allergy Clin Immunol 2013;131:1288-96.
Desensitization of FcεRI-bearing mast cells and basophils
MECHANISMS OF ALLERGEN-SPECIFIC IMMUNOTHERAPY
• Desensitization of FceRI
• T cell responses
• Allergen-specific IgE and IgG4 responses
• Regulation of mast cells, basophils, and eosinophils
A. Wesley Burks et al, J Allergy Clin Immunol 2013;131:1288-96.
T-cell responses
• IL-10 increase is similar to the mechanisms of allergen tolerance observed in high-dose allergen exposure models
• TGF-b production increases during AIT for mucosal allergies but not
during AIT for venom allergy
Major role in inhibiting allergic disorders
A. Wesley Burks et al, J Allergy Clin Immunol 2013;131:1288-96.
Middleton allergy 8th edition
Middleton allergy 8th edition
MECHANISMS OF ALLERGEN-SPECIFIC IMMUNOTHERAPY
• Desensitization of FceRI
• T cell responses
• Allergen-specific IgE and IgG4 responses
• Regulation of mast cells, basophils, and eosinophils
A. Wesley Burks et al, J Allergy Clin Immunol 2013;131:1288-96.
• No evidence that it induces B-cell tolerance • Serum-specific IgE levels often transiently increase after AIT and
then gradually decrease over months or years of continued treatment
• Poorly correlated with clinical improvement after AIT A. Wesley Burks et al, J Allergy Clin Immunol 2013;131:1288-96.
• Increases in specific IgG4 levels accompany clinical improvement with AIT
• IgG4 is considered a blocking antibody • inhibits allergen-induced and IgE-mediated release • IgE-facilitated allergen presentation to T cells • Allergen induced boost of memory IgE production
A. Wesley Burks et al, J Allergy Clin Immunol 2013;131:1288-96.
Nature Review, 2006
MECHANISMS OF ALLERGEN-SPECIFIC IMMUNOTHERAPY
• Desensitization of FceRI
• T cell responses
• Allergen-specific IgE and IgG4 responses
• Regulation of mast cells, basophils, and eosinophils
A. Wesley Burks et al, J Allergy Clin Immunol 2013;131:1288-96.
Regulation of mast cells, basophils, and eosinophils
• IL-10 – downregulates eosinophil function and
activity
– suppresses IL-5 production by human T cells
• Treg cells – inhibit the FcεRI-dependent mast cell
degranulation through Treg cell–mast cell contact, which leads to increased cyclic AMP concentrations and reduced Ca++ influx
A. Wesley Burks et al, J Allergy Clin Immunol 2013;131:1288-96.
T reg cell • Reduced Ca++ influx • In creased cyclic
AMP
Middleton allergy 8th edition
Middleton allergy 8th edition
CURRENT STATUS OF ALLERGEN-SPECIFIC IMMUNOTHERAPY
SLIT vs SCIT • Both reducing topical steroid use and
improve SCORAD in AD • SCIT: preventing venom induced
anaphylaxis • SLIT has a better safety profile than
SCIT • SCIT: 0.1% reported rate systemic
reaction, 86% within 30 min • SLIT: local reactions fist few days and
spontaneous resolve
A. Wesley Burks et al, J Allergy Clin Immunol 2013;131:1288-96.
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
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
• 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
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
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
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
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= 0.03
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
• Benefits last after discontinuation of therapy is not clear
• Sustained allergens exposure likely aids in maintaining tolerance
• Thus it is possible that for certain allergy indications, such as food allergy, maintaining immune tolerance is only feasible if allergen exposure is ongoing.
MECHANISMS OF ALLERGEN-SPECIFIC IMMUNOTHERAPY
A. Wesley Burks et al, J Allergy Clin Immunol 2013;131:1288-96.
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.