allergy immunotherapy (mechanisms)

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

Allergic inflammation

Nature Review, 2006

Kenny Y. Kwong et al. Advances in Pediatrics 60 (2013) 141–165

Immune Tolerance

• Immature lymphocyte

• Negative selection

Central tolerance

• CD4+ T cell/ T helper cell

Peripheral tolerance

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

Central: T-cell

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

“Anergy”

Lack of complete

signal for T cell

activation

Inhibitory receptor CTLA-4

“Suppression”

Regulatory T cell

• Thymus

• Peripheral

lymphoid organs

Immature/ resting DC

The development and survival of these regulatory T cells require IL-2 and the

transcription factor FoxP3

Regulatory T-cell

Middleton allergy 8th edition

Treg cells directly or indirectly suppress all other effector T cell subsets

“Deletion”

T cells that recognize self antigens

in the absence of costimulation

may activate Bim, resulting in

apoptosis by the mitochondrial

pathway

“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

Multiple mechanisms of immune tolerance

• Desensitization of FcRI

• T cell responses

• Allergen-specific IgE and IgG4 responses

• Regulation of mast cells, basophils, and eosinophils

Desensitization of FcεRI-bearing mast cells and basophils

• Desensitization of FceRI

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

• 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

Nature Review, 2006

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

T reg cell • Reduced Ca++ influx • In creased cyclic

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

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

Few proinflammatory cell

3 subsets of dendritic cells

• Langerhans cells (LCs)

• oral epithelium

• Myeloid APCs (MDC)

• macrophage-like cells

• lamina propria

• Plasmacytoid DCs (pDCs) • subepithelial tissues

• 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

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

Mast cell: MC

Langerhans: LC

MCs appear to be closer to

the mucosal surface in

lingual tissues SLIT is

often associated with tongue

edemas

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

The highest FcRI

expression could be

detected on oLC from the vestibulum

Macrophage: MC

Langerhans: LC

different mucosal regions

such as the vestibulum

might represent alternative

SLIT application sites with potent allergen uptake

• 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

• 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

• 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

• 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

• 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

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

p < 0.05 p < 0.05

p < 0.005

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

• 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.

FUTURE OF AIT

• not all patients will see improvement

• carries the risk of anaphylaxis

• number of administrations and the duration of the therapeutic course

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