Sublingual immunotherapy

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Sublingual immunotherapy

Presented by Theerapan Songnuy, MD.

Sep14, 2012

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Sublingual immunotherapy

  1. 1. Sublingual ImmunotherapyMechanism and Applications on Food Allergy Theerapan Songnuy M.D.
  2. 2. Sublingual Immunotherapy ( SLIT)• Definition• Mechanism• Clinical application• Future trend
  3. 3. Definition• Allergen specific immunotherapy : - administering gradually increasing doses of the specific allergen to reduce the clinical reaction - the only treatment focusing the causes of hypersensitivityMarseglia 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
  4. 4. Definition• Subcutaneous immunotherapy ( SCIT) - traditional route but risk for systemic reaction• Sublingual immunotherapy ( SLIT) - non injection route for specific immuno- therapyMarseglia 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
  5. 5. 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 initiationMorris 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
  6. 6. Mechanism of SLITScadding G, MRCPa,b,*, Durham SR, Immunol Allergy Clin N Am 31 (2011)
  7. 7. 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 SLITNovak N, Haberstok J, Bieber T, et al. The immune privilege of the oral mucosa.Trends Mol Med 2008;14(5):191–8 .
  8. 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 toleranceScadding G & Durham S. Mechanism of Sublingual Immunotherapy. Journal of Asthma. 2009.46;4:332-334
  9. 9. 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 activationScadding G & Durham S. Mechanism of Sublingual Immunotherapy. Journal of Asthma. 2009.46;4:332-334
  10. 10. Immune Changes Associated with SLITPro-inflammatory Cells : - Reduced recruitment & activation of inflammatory cells in skin, nose, eye & mucosaT-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 cytokinesScadding G & Durham S. Mechanism of Sublingual Immunotherapy. Journal of Asthma. 2009.46;4:332-334
  11. 11. 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
  12. 12. 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.
  13. 13. MethodsPrimary end point : reaction threshold to peanut ingestion after 12 months of therapySecondary 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
  14. 14. MethodsInclusion 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/LExclusion criteria - severe anaphylaxis to peanut or need ICU careKim EH et al.Journal of Allergy and Clinical Immunology. 2011.127;3: 640-646.e1
  15. 15. 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 coloringKim EH et al.Journal of Allergy and Clinical Immunology. 2011.127;3: 640-646.e1
  16. 16. 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 swallowedKim EH et al.Journal of Allergy and Clinical Immunology. 2011.127;3: 640- 646.e1
  17. 17. 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 wkKim EH et al.Journal of Allergy and Clinical Immunology. 2011.127;3: 640-646.e1
  18. 18. 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 monthsDouble-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 occursKim EH et al.Journal of Allergy and Clinical Immunology. 2011.127;3: 640-646.e1
  19. 19. 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 levelKim EH et al.Journal of Allergy and Clinical Immunology. 2011.127;3: 640-646.e1
  20. 20. 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 requiredKim EH et al.Journal of Allergy and Clinical Immunology. 2011.127;3: 640-646.e1
  21. 21. 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.
  22. 22. 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 markersKeet CA et al. J Allergy Clin Immunol 2012;129:448-55.
  23. 23. 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
  24. 24. 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 mgKeet CA et al. J Allergy Clin Immunol 2012;129:448-55
  25. 25. Keet CA et al. J Allergy Clin Immunol 2012;129:448-55
  26. 26. Keet CA et al. J Allergy Clin Immunol 2012;129:448-55
  27. 27. Keet CA et al. J Allergy Clin Immunol 2012;129:448-55
  28. 28. Keet CA et al. J Allergy Clin Immunol 2012;129:448-55
  29. 29. 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
  30. 30. Results1. Desensitization vs tolerance - tolerance found in all group, no difference2. Symptoms with dosing -Significant difference in rate of respiratory, GI, & multisystem symptom between SLIT and OIT - No difference reaction between OITA and OITBKeet CA et al. J Allergy Clin Immunol 2012;129:448-55
  31. 31. 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 T3Keet CA et al. J Allergy Clin Immunol 2012;129:448-55
  32. 32. Sublingual immunotherapy for hazelnut food allergy: A randomized, double-blind, placebo-controlled study with a standardized hazelnut 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 -
  33. 33. ResultsErnesto Enrique et al .J Allergy Clin Immunol -
  34. 34. Ernesto Enrique et al .J Allergy Clin Immunol -
  35. 35. Ernesto Enrique et al .J Allergy Clin Immunol -
  36. 36. Ernesto Enrique et al .J Allergy Clin Immunol -
  37. 37. 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 groupErnesto Enrique et al .(J Allergy Clin Immunol -
  38. 38. 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 routePfaar 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.
  39. 39. Thank You Very Much

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