Abstract
Food allergy is an important medical problem with increasing prevalence throughout the world. Different approaches of food immunotherapy are being investigated including oral, epicutaneous and sublingual routes. Sublingual immunotherapy (SLIT) for food allergy involves placement of glycerinated allergen under the tongue daily to achieve allergen-specific desensitization. SLIT has been studied in the treatment of hazelnut, peach, apple, milk and peanut allergies with substantial focus on the treatment of peanut allergy. Phase II studies have shown SLIT for treatment of peanut allergy increases the tolerated dose of peanut by a substantial margin with fewer and less severe side effects than other modalities. This review discusses the mechanisms of SLIT, early studies of its use in food allergy and larger randomized controlled trials for treatment of peanut allergy. Future directions using the mechanisms involved in SLIT include oral mucosal immunotherapy for peanut allergy.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1. . Food allergy: a review and update on epidemiology, pathogenesis, diagnosis, prevention and management. J. Allergy Clin. Immunol. 141(1), 41–58 (2018).
- 2. The prevalence of food allergy and other allergic diseases in early childhood in a population-based study: healthNuts age 4-year follow-up. J. Allergy Clin. Immunol. 140(1), 145–153.e8 (2017).
- 3. Prevalence and severity of food allergies among US adults. JAMA Netw. Open 2(1), e185630 (2019).
- 4. . Prevalence of self-reported food allergy in the National Health and Nutrition Examination Survey (NHANES) 2007–2010. J. Allergy Clin. Immunol. 132(5), 1216–1219.e5 (2013).
- 5. . Food allergy: riding the second wave of the allergy epidemic: the food allergy epidemic. Pediatr. Allergy Immunol. 22(2), 155–160 (2011).
- 6. Allergic reactions to foods in preschool-aged children in a prospective observational food allergy study. Pediatrics 130(1), e25–e32 (2012).
- 7. . Quality of life in childhood, adolescence and adult food allergy: patient and parent perspectives. Clin. Exp. Allergy 47(4), 530–539 (2017).
- 8. Accidental food allergy reactions: products and undeclared ingredients. J. Allergy Clin. Immunol. 142(3), 865–875 (2018).
- 9. Frequency, severity and causes of unexpected allergic reactions to food: a systematic literature review. Clin. Exp. Allergy 45(2), 347–367 (2015).
- 10. . Assessment of quality of life in children with peanut allergy. Pediatr. Allergy Immunol. 14(5), 378–382 (2003).
- 11. Randomized trial of peanut consumption in infants at risk for peanut allergy. N. Engl. J. Med. 372(9), 803–813 (2015).
- 12. Randomized trial of introduction of allergenic foods in breast-fed infants. N. Engl. J. Med. 374(18), 1733–1743 (2016).
- 13. . Natural resolution of peanut allergy: a 12-year longitudinal follow-up study. J. Allergy Clin. Immunol. Pract. 1(5), 528–530.e4 (2013).
- 14. . The challenges of preventing food allergy. Ann. Allergy Asthma Immunol. 121(3), 313–319 (2018).
- 15. . Treatment of anaphylactic sensitivity to peanuts by immunotherapy with injections of aqueous peanut extract1. J. Allergy Clin. Immunol. 99(6), 744–751 (1997).
- 16. . Food allergy immunotherapy: OIT and EPIT. Allergy 75(6), 1337–1346 (2020).
- 17. . Treatment for food allergy. J. Allergy Clin. Immunol. 141(1), 1–9 (2018).
- 18. . Next-generation approaches for the treatment of food allergy. Curr. Allergy Asthma Rep. 19(1), 5 (2019).
- 19. The PALISADE Group of Clinical Investigators. AR101 oral immunotherapy for peanut allergy. N. Engl. J. Med. 379(21), 1991–2001 (2018).
- 20. . Drug approved to aid youths with peanut allergy. JAMA 323(9), 817 (2020).
- 21. Oral immunotherapy for peanut allergy (PACE): a systematic review and meta-analysis of efficacy and safety. Lancet 393(10187), 2222–2232 (2019).
- 22. Adverse reactions during peanut oral immunotherapy home dosing. J. Allergy Clin. Immunol. 124(6), 1351–1352 (2009).
- 23. . Immune mechanisms of sublingual immunotherapy. Curr. Allergy Asthma Rep. 14(11), 473 (2014).
- 24. . Mechanisms of sublingual immunotherapy. J. Asthma 46(4), 322–334 (2009).
- 25. Phl p 5 resorption in human oral mucosa leads to dose-dependent and time-dependent allergen binding by oral mucosal Langerhans cells, attenuates their maturation and enhances their migratory and TGF-β1 and IL-10–producing properties. J. Allergy Clin. Immunol. 126(3), 638–645.e1 (2010).
- 26. Toll-like receptor 4 ligation enforces tolerogenic properties of oral mucosal Langerhans cells. J. Allergy Clin. Immunol. 121(2), 368–374.e1 (2008).
- 27. Sublingual grass pollen immunotherapy is associated with increases in sublingual Foxp3-expressing cells and elevated allergen-specific immunoglobulin G4, immunoglobulin A and serum inhibitory activity for immunoglobulin E-facilitated allergen binding to B cells.. Clin. Exp. Allergy 40(4), 598–606 (2010).
- 28. . Sublingual immunotherapy induces IL-10–producing T regulatory cells, allergen-specific T-cell tolerance and immune deviation. J. Allergy Clin. Immunol. 120(3), 707–713 (2007).
- 29. Grass tablet sublingual immunotherapy downregulates the TH2 cytokine response followed by regulatory T-cell generation. J. Allergy Clin. Immunol. 133(1), 130–138.e2 (2014).
- 30. Grass pollen immunotherapy induces mucosal and peripheral IL-10 responses and blocking IgG activity. J. Immunol. 172(5), 3252–3259 (2004).
- 31. . IgE-blocking antibodies following SLIT with recombinant Mal d 1 accord with improved apple allergy. J. Allergy Clin. Immunol. S0091674920304188
doi: 10.1016/j.jaci.2020.03.015 (2020). - 32. Sublingual grass allergen tablet immunotherapy provides sustained clinical benefit with progressive immunologic changes over 2 years. J. Allergy Clin. Immunol. 121(2), 512–518.e2 (2008).
- 33. Synchronous immune alterations mirror clinical response during allergen immunotherapy. J. Allergy Clin. Immunol. 141(5), 1750–1760.e1 (2018).
- 34. Effect of 2 years of treatment with sublingual grass pollen immunotherapy on nasal response to allergen challenge at 3 years among patients with moderate to severe seasonal allergic rhinitis: the GRASS randomized clinical trial. JAMA 317(6), 615 (2017).
- 35. SQ-standardized sublingual grass immunotherapy: confirmation of disease modification 2 years after 3 years of treatment in a randomized trial. J. Allergy Clin. Immunol. 129(3), 717–725.e5 (2012).
- 36. . Severe anaphylaxis to kiwi fruit: immunologic changes related to successful sublingual allergen immunotherapy. J. Allergy Clin. Immunol. 111(6), 1406–1409 (2003).
- 37. . Life-threatening anaphylaxis to kiwi fruit: protective sublingual allergen immunotherapy effect persists even after discontinuation. J. Allergy Clin. Immunol. 119(2), 507–508 (2007).
- 38. Sublingual immunotherapy for hazelnut food allergy: a randomized, double-blind, placebo-controlled study with a standardized hazelnut extract. J. Allergy Clin. Immunol. 116(5), 1073–1079 (2005).
- 39. Randomized double-blind, placebo-controlled trial of sublingual immunotherapy with a Pru p 3 quantified peach extract. Allergy 64(6), 876–883 (2009).
- 40. Efficacy and safety of 4 months of sublingual immunotherapy with recombinant Mal d 1 and Bet v 1 in patients with birch pollen–related apple allergy. J. Allergy Clin. Immunol. 141(3), 1002–1008 (2018).
- 41. The safety and efficacy of sublingual and oral immunotherapy for milk allergy. J. Allergy Clin. Immunol. 129(2), 448–455.e5 (2012). • Only study to compare outcomes and side effects between oral immunotherapy and sublingual immunotherapy (SLIT) in treatment of milk allergy.
- 42. Sublingual immunotherapy for peanut allergy: a randomized, double-blind, placebo-controlled multicenter trial. J. Allergy Clin. Immunol. 131(1), 119–127.e7 (2013). •• First randomized controlled trial of SLIT for the treatment of peanut allergy.
- 43. Sublingual immunotherapy for peanut allergy: long-term follow-up of a randomized multicenter trial. J. Allergy Clin. Immunol. 135(5), 1240–1248.e3 (2015).
- 44. Oral Immunotherapy for treatment of egg allergy in children. N. Engl. J. Med. 367(3), 233–243 (2012).
- 45. A randomized, double-blind, placebo-controlled pilot study of sublingual versus oral immunotherapy for the treatment of peanut allergy. J. Allergy Clin. Immunol. 135(5), 1275–1282.e6 (2015). • Randomized controlled trial comparing SLIT and oral immunotherapy in treatment of peanut allergy.
- 46. Sublingual immunotherapy for peanut allergy: clinical and immunologic evidence of desensitization. J. Allergy Clin. Immunol. 127(3), 640–646.e1 (2011).
- 47. Long-term sublingual immunotherapy for peanut allergy in children: clinical and immunologic evidence of desensitization. J. Allergy Clin. Immunol. 144(5), 1320–1326.e1 (2019). •• Randomized controlled trial of SLIT for the treatment of peanut allergy in young children.
- 48. Sustained unresponsiveness to peanut in subjects who have completed peanut oral immunotherapy. J. Allergy Clin. Immunol. 133(2), 468–475.e6 (2014).
- 49. . Understanding caregiver goals, benefits and acceptable risks of peanut allergy therapies. Ann. Allergy Asthma Immunol. 121(5), 575–579 (2018). • Detailed report of caregiver goals and expectations of food allergy therapy.
- 50. . Quantitative assessment of the safety benefits associated with increasing clinical peanut thresholds through immunotherapy. J. Allergy Clin. Immunol. Pract. 6(2), 457–465.e4 (2018).
- 51. Novel baseline predictors of adverse events during oral immunotherapy in children with peanut allergy. J. Allergy Clin. Immunol. 139(3), 882–888.e5 (2017). • Retrospective analysis of adverse effects of oral immunotherapy.
- 52. . Local side effects of sublingual and oral immunotherapy. J. Allergy Clin. Immunol. Pract. 5(1), 13–21 (2017).
- 53. . Real-life compliance and persistence among users of subcutaneous and sublingual allergen immunotherapy. J. Allergy Clin. Immunol. 132(2), 353–360.e2 (2013).
- 54. . Adherence to sublingual immunotherapy. Curr. Allergy Asthma Rep. 16(2), 12 (2016).
- 55. . Causes of SLIT discontinuation and strategies to improve the adherence: a pragmatic approach. Allergy 68(9), 1193–1195 (2013).
- 56. . Oral mucosal immunotherapy for allergic rhinitis: a pilot study. Allergy Rhinol. 7(1), 21–28 (2016).
- 57. Distribution of Langerhans cells and mast cells within the human oral mucosa: new application sites of allergens in sublingual immunotherapy? Allergy 63(6), 720–727 (2008).
- 58. . Allergy immunotherapy adherence and delivery route: location does not matter. J. Allergy Clin. Immunol. Pract. 2(2), 156–160.e2 (2014).