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
Immune Changes Associated with SLIT
• 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
Scadding G & Durham S. Mechanism of Sublingual Immunotherapy. Journal of Asthma. 2009.46;4:332-334
Immune Changes Associated with SLIT
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
Scadding G & Durham S. Mechanism of Sublingual Immunotherapy. Journal of Asthma. 2009.46;4:332-334
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
Kim EH et al.Journal of Allergy and Clinical Immunology. 2011.127;3: 640-646.e1
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
Kim EH et al.Journal of Allergy and Clinical Immunology. 2011.127;3: 640-646.e1
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
Kim EH et al.Journal of Allergy and Clinical Immunology. 2011.127;3: 640-646.e1
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
Kim EH et al.Journal of Allergy and Clinical Immunology. 2011.127;3: 640-646.e1
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
Kim EH et al.Journal of Allergy and Clinical Immunology. 2011.127;3: 640-646.e1
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
Kim EH et al.Journal of Allergy and Clinical Immunology. 2011.127;3: 640-646.e1
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.
The Safety and Efficacy of Sublingual and Oral Immunotherapy for Milk Allergy
• 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.
The Safety and Efficacy of Sublingual and Oral Immunotherapy for Milk Allergy
• 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
Keet CA et al. J Allergy Clin Immunol 2012;129:448-55
Keet CA et al. J Allergy Clin Immunol 2012;129:448-55
Keet CA et al. J Allergy Clin Immunol 2012;129:448-55
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.
Keet CA et al. J Allergy Clin Immunol 2012;129:448-55
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
Keet CA et al. J Allergy Clin Immunol 2012;129:448-55
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
Keet CA et al. J Allergy Clin Immunol 2012;129:448-55
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.
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.
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