sublingual immunotherapy

Sublingual ImmunotherapyMechanism and Applications on Food

Allergy

Theerapan Songnuy M.D.

Sublingual Immunotherapy ( SLIT)

• Definition• Mechanism• Clinical application• Future trend

Definition

• Allergen specific immunotherapy :

- administering gradually increasing doses of the specific allergen to reduce the clinical reaction

- the only treatment focusing the causes of hypersensitivity

Marseglia G L, Incorvaia C, Rosa M L, Frati F & Marcucci F. Sublingual immunotherapy in children : facts and needs. Italian Journal of Pediatrics 2009, 35:31

Definition

• Subcutaneous immunotherapy ( SCIT)

- traditional route but risk for systemic

reaction• Sublingual immunotherapy ( SLIT)

- non injection route for specific immuno-

therapy

Marseglia G L, Incorvaia C, Rosa M L, Frati F & Marcucci F. Sublingual immunotherapy in children : facts and needs. Italian Journal of Pediatrics 2009, 35:31

Why SLIT ?• SCIT : not widely accepted due to

- Possible severe symptoms

- Inconvenience of injection

- Frequent office visits

Less than 5% of all allergic patients receive immunotherapy

Compliance is even poorer : more than 2/3 of patients dropped out within a year of initiation

Morris MS., Lowery A., Theodoropoulos DS., Duquette RD. & Morris DL.

Quality of Life Improvement with Sublingual Immunotherapy : A Prospective Study of Efficacy. Journal of Allergy. 2012, Article ID 253879, 6 pages doi: 10.1155/2012/253879.

Brown D., Hankin C., Scott D. et al. Characteristic Association with Premature Discontinuation of Allergen Immunotherapy among Children and Adults: Finding from a large, Single Specialty Allergy Practice . Journal of Allergy and Clinical Immunology . 2009. 123;3: 728.

Mechanism of SLIT

Scadding G, MRCPa,b,*, Durham SR, Immunol Allergy Clin N Am 31 (2011) 191–209 doi:10.1016/j.iac.2011.02.005

Mechanism of SLIT• oral mucosa has a degree of immune privilege & potentially

tolerogenic antigen-presenting cells & T cells

• Intraoral environment is protected from inflammatory responses by

high levels of secretory IgA, antimicrobial peptides in saliva, and commensal bacteria

• All factors may be important in facilitating tolerogenic responses to SLIT

Novak N, Haberstok J, Bieber T, et al. The immune privilege of the oral mucosa.

Trends Mol Med 2008;14(5):191–8.

Immune Changes Associated with SLIT

• Allergen specific immunotherapy reduces immediate and late-phase allergen-induced symptoms

• Processing by humoral and cellular mechanism

• Immune mechanism leads to clinical tolerance

Scadding G & Durham S. Mechanism of Sublingual Immunotherapy. Journal of Asthma. 2009.46;4:332-334


• Antibody Responses

- After SLIT initiation, decreasing serial IgE levels & prevent seasonal sIgE rising

- Eliciting IgG1, IgG4 “ blocking Ab” by competing with IgE for allergen binding

- SLIT also down regulate mast cell & B cell activation



Pro-inflammatory Cells :

- Reduced recruitment & activation of inflammatory cells in skin, nose, eye & mucosa

T-Cell Responses :

- Shifting from Th2 >>> Th1 with the stimulation of IFN gamma – producing T lymphocyte

- Inducing Treg ( inhibit effector mechanism)

- Treg1 : produce IL-10 & TGF-beta

- IL-10 : decrease IgE production, inhibit Th2 cytokines

- TGF-beta : enhance IgG4 & IgA production, inhibit Th2 cytokines


SLIT applying on Food Allergy

• Sublingual Immunotherapy for Peanut Allergy: Clinical and Immunologic Evidence of Desensitization

- Peanut is one of the most common

and severe food allergy*

- Less than 20% will outgrow the allergy

naturally

- Current standard of care is strict avoidance

*Skolnick HS, Conover-Walker MK, Koerner CB, Sampson HA, Burks W, Wood RA. The natural

history of peanut allergy. J Allergy Clin Immunol 2001;107:367-74.

Sublingual Immunotherapy for Peanut Allergy: Clinical and Immunologic Evidence of Desensitization

• SCIT is used successfully in allergic rhinitis & asthma• But for food allergy, unacceptable due to systemic reaction*• Oral immunotherapy ( OIT)• The first study using SLIT in treatment of peanut allergy In

children• Double-blind, placebo-controlled trial• Aim to evaluate safety & efficacy of peanut SLIT after 12

months of therapy and observe immunologic changes

*Nelson HS, Lahr J, Rule R, Bock A, Leung D. Treatment of anaphylactic sensitivity to peanuts by immunotherapy with injections of aqueous peanut extract. J Allergy Clin Immunol 1997; 124: 292-300, e1-97.

Methods

Primary end point : reaction threshold to

peanut ingestion after 12 months of therapy

Secondary end point : frequency, severity, of side effect to dosing, immunologic changing(sIgE, IgG4 level, basophil activation, skin test,cytokines level, interferon gamma, Treg cells)

Kim EH et al.Journal of Allergy and Clinical Immunology. 2011.127;3: 640-646.e1

Methods

Inclusion criteria

- Participants aged 1-11 y

- physician- documented clinical history of reaction to peanut within 60 min of ingestion

- CAP-FEIA peanut sIgE > 7 kU/L

Exclusion criteria

- severe anaphylaxis to peanut or need ICU care


Methods

- Peanut and placebo sublingual drops from

Greer Lab.

Treatment gr. : crude peanut extract (1:20w/v)

dissolved in 0.2% phenol & 50%-55%

glycerinated saline ( conc. 5000 ug/ml)

Ara h2 protein conc. 6 %

Placebo gr. : glycerinated saline & phenol with caramel coloring


SLIT PROTOCOL

- Strict peanut-free diet

- Carry on epinephrine autoinjector

- Restrict eating 15 min before & 30 min after dosing

- Drug was administered sublingually held 2min. then swallowed


SLIT PROTOCOL

Escalation phase

- initial dose is 0.25 ug of peanut protein,

2-hr observation time

- return for 13 biweekly visits

- dose were increased 25-100% until max.

of 2,000 ug of peanut protein

- after each visit, continuing the same dose

at home for 2 wk Kim EH et al.Journal of Allergy and Clinical Immunology. 2011.127;3: 640-646.e1

Sublingual Immunotherapy for Peanut Allergy: Clinical and Immunologic Evidence

of Desensitization• Maintenance phase

- the 2000-ug dose was used based on pilot study

- continue daily dose at home for 6 months

Double-blind placebo-controlled food challenge

- 9 –increasing dose peanut protein mixed with vehicle food

- doses were given q 20 min until 2500 gm

( cumulative dose)

- placebo portion using oat flour mixed in vehicle food

- the outcome was defined as a cumulative dose ingested

before symptom occurs


Results

• Participants in peanut SLIT gr. increase reaction threshold after ingesting a median cumulative dose of 1710 gm of peanut protein

• Clinically significant to protect from accidental ingestion of peanut ( 100 gm)

• Association between DBPCFC with a lower peanut sIgE level


Results

• Decreased mast cell and basophil reactivity• Peanut-sIgE decrease• Peanut-sIgG increase• Down-regulation of Th 2 response ( decrease

IL-5 production)• Side effect ; oropharyngeal itching ( 9.3% of

doses )• Epinephrine not required


The Safety and Efficacy of Sublingual and Oral Immunotherapy for Milk Allergy

• To compare

- safety and efficacy of OIT and SLIT

for treatment of cow’s milk allergy

- effect of withdrawal therapy after 1 and 6 wk

- mechanistic changes associated with therapy ( sIgE,

sIgG4, skin test response, basophil function & intracellular signaling

- Double-blind, placebo-controlled trial

Keet CA et al. J Allergy Clin Immunol 2012;129:448-55.


• Methods

- Open-label randomized study

- primary end point : ability to tolerate at least

10-fold more milk protein compared with

baseline ( duration 15 months)

- secondary end point:

-desensitization maintains after 1, 6 wk off treatment

- clinical response rate

- serious adverse events

- changes in biological markers

Keet CA et al. J Allergy Clin Immunol 2012;129:448-55.


• Participants

- aged 6-21 y from pediatric allergy clinic,

Johns Hopkins Hospital & Duke U Medical

Centre

- Inclusion criteria: documented history CMA,

sIgE to CM> 0.35 Ku/l , SPT, DBPCFC

-Exclusion criteria: severe persistent asthma,

pt. on fluticasone, non-allergic medical problem

severe anaphylaxis to CM etc.

Keet CA et al. J Allergy Clin Immunol 2012;129:448-55

SLIT Dosing

• Initial dosing

- low-dose SLIT

- continue at home, daily home diary• Continued escalation

- patient returns q 1-2 wk for dose increase

- At 4-weekly SLIT, randomized to 3 gr.

1. OITA target dose 2 gm

2. OITB target dose 1 gm

3. SLIT goal dose of 7 mg Keet CA et al. J Allergy Clin Immunol 2012;129:448-55

Results

• Challenge threshold after therapy

- increased at least 10 times compared to

baseline, more common in OIT gr.


Results

1. Desensitization vs tolerance

- tolerance found in all group, no difference

2. Symptoms with dosing

-Significant difference in rate of respiratory,

GI, & multisystem symptom between SLIT and OIT

- No difference reaction between OITA and OITB


Results

• Serologic & SPT measures

- CM-sIgE level decreased in OITA, OITB by T5 but not change in SLIT/SLIT

- CM-sIgG4 level increased from all gr. From T1

- SPT decreased in all gr. by T3


Sublingual immunotherapy for hazelnutfood allergy: A randomized, double-blind,

placebo-controlled study with a standardizedhazelnut extract

• to evaluate the efficacy and tolerance of SLIT with a standardized hazelnut extract in patients allergic to hazelnut

• a randomized, double-blind, placebo-controlled study• Inclusion criteria : a history of hazelnut allergy and positive SPT

and double-blind placebo-controlled food challenge results. • randomly assigned patients into 2 treatment groups (hazelnut

immunotherapy or placebo)• Efficacy was assessed by DBPCFC after 8 to 12 weeks of

treatment.• specific IgE, IgG4, and serum cytokines before and after treatment.

Ernesto Enrique et al .J Allergy Clin Immunol 2005;116:1073-9.)

Results

Ernesto Enrique et al .J Allergy Clin Immunol 2005;116:1073-9.

Ernesto Enrique et al .J Allergy Clin Immunol 2005;116:1073-9.

Ernesto Enrique et al .J Allergy Clin Immunol 2005;116:1073-9

Results

• Twenty-three patients were enrolled and divided into 2 treatment groups.

• Twenty-two patients reached the planned maximum dose at 4 days. • Systemic reactions : 0.2% of the total doses administered.• Mean hazelnutquantity provoking objective symptoms increased

from 2.29 g to 11.56 g (P = .02; active group) versus 3.49 g to 4.14 g (placebo; NS).

• 50% of patients who underwent active treatment reached the highest dose (20 g), but only 9% in the placebo.

• Laboratory : increase in IgG4 and IL-10 levels after immunotherapy in only the active group

Ernesto Enrique et al .(J Allergy Clin Immunol 2005;116:1073-9.)

Future Trends of SLIT• Adjuvants and Vector System for Sublingual

Vaccine

- Act as immunopotentiator

- could reduce the dose of allergen or

simplify immunization scheme

- In human, Monophosphoryl lipid A

(adjuvant), a TLR4 ligand-inducing Th1 response has been tested via sublingual route

Pfaar O.,Barth C., Jaschke C., Hormann K. & Klimek. Sublingual Allergen-Specific Immunotherapy adjuvanted with monophosphoryl lipid A : a phase I/IIa study . International Archives of Allergy and Immunology. 2010. 154;4:336-344.

Thank You Very Much

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