Sublingual immunotherapy for inhalant allergens

Mechanism of Sublingual

Immunotherapy(SLIT)

For Inhalant Allergens

Jaichat Mekaroonkamol, MD.

SCIT SLIT

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

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

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

John R. Gordon et al. Frontiers in immunology. January 2014

Helper T cell (Th) polarization by dendritic cells (DCs). Depending on • Type of antigen • Dose • Tissue environment where antigen is

first introduced

John R. Gordon et al. Frontiers in immunology. January 2014

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 >

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

• 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

Allam et al. Allergy: 2011; 532–539.

• 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

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

• 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.

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.

• 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

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

P= 0.0001

P= 0.02

P= 0.0001

P= 0.01

P= 0.03

P= 0.003

P= 0.0001

P= 0.004 P= 0.002

P= 0.03

IgE IgG1

• 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.

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

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

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

Biomarkers for SLIT efficacy

Short-term SLIT (hours to <1 wk)

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

Short-term SLIT (hours to <1 wk)

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

C1Q and STAB1 represent candidate biomarkers of

early efficacy of SLIT as the hallmark of a regulatory

innate immune response predictive of clinical tolerance.

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.

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