Promoting Tolerance to Peanut in High-Risk Children (LEAP)
Evelina Children's Hospital | London, United Kingdom
The prevalence of peanut allergy has doubled over the past 10 years in countries that advocate avoidance of peanuts during pregnancy, lactation and infancy. Peanut allergy now affects approximately 1.5% of young children. There are 2 main explanations for this failure to prevent peanut allergies through avoidance measures: 1. Sensitisation to food allergens may not occur through oral exposure, but rather through other routes such as topical cutaneous exposure, and 2. Early oral exposure may be required to prevent the development of peanut allergy through oral tolerance induction. UK and US guidelines had previously discouraged oral exposure during pregnancy, breastfeeding and infancy. These guidelines may have promoted allergic sensitisation by creating a situation where there is environmental cutaneous exposure in the absence of early oral tolerance induction. This imbalance in the routes of allergen presentation may favour the development of allergic sensitisation.
The primary aim of our study is to determine which is the best strategy for reducing peanut allergy, early high dose consumption of peanut protein or avoidance. Secondary aims are to compare the development of sensitisation to peanuts, the development of tree nut allergy at age 5, sensitisation to control allergens (house dust mite and egg) and immunological assays.
Of the children who avoided peanut, 17% developed peanut allergy by the age of 5 years. Remarkably, only 3% of the children who were randomized to eating the peanut snack developed allergy by age 5. Therefore, in high-risk infants, sustained consumption of peanut beginning in the first 11 months of life was highly effective in preventing the development of peanut allergy.
This randomized parallel group study enrolled high risk infants. Half the children were randomised to early high dose consumption of peanut snack between age 4-11 months and the other half were randomized to complete dietary peanut avoidance. All 640 study participants were enrolled as of May 2009.
Immunological assays will focus on alterations in the function of peanut-specific T cells (cytokine production, precursor cell frequency), the development of regulatory T cells subsets, the importance of IgE dependent facilitated antigen presentation and the development of IgG4 as a “blocking antibody.” Peptide specific IgE and IgG epitopes in the different tolerant and allergic states will also be studied. This will allow us to address both the clinical and immunological specificity of oral tolerance induction, study the underlying mechanisms of oral tolerance and provide a new strategy to prevent allergic disease.
Du Toit G, Roberts G, Sayre PH, Bahnson HT, Radulovic S, Santos AF, Brough HA, Phippard D, Basting M, Feeney M, Turcanu V, Sever ML, Gomez Lorenzo M, Plaut M, Lack G; LEAP Study Team. (2014) Randomized trial of peanut consumption in infants at risk for peanut allergyN Engl J Med, 372(9), 803-813. DOI: 10.1056/NEJMoa1414850 PMID: 25705822 PMCID: PMC4416404 [PubMed] [Reprint]
Du Toit G, Sayre PH, Roberts G, Lawson K, Sever ML, Bahnson HT, Fisher HR, Feeney M, Radulovic S, Basting M, Plaut M, Lack G; Immune Tolerance Network LEAP Study Team. (2016) The allergen-specificity of early peanut consumption and the impact on the development of allergic disease in the LEAP Study CohortJ Allergy Clin Immunol, (), . DOI: 10.1016/j.jaci.2017.09.034 PMID: 29097103 PMCID: [PubMed] [Reprint]
Du Toit G, Sayre PH, Roberts G, Sever ML, Lawson K, Bahnson HT, Brough HA, Santos AF, Harris KM, Radulovic S, Basting M, Turcanu V, Plaut M, Lack G; Immune Tolerance Network LEAP-On Study Team. (2015) Effect of Avoidance on Peanut Allergy after Early Peanut ConsumptionN Engl J Med, 14(374), 1435-43. DOI: 10.1056/NEJMoa1514209 PMID: 26942922 PMCID: [PubMed] [Reprint]
Du Toit G, Roberts G, Sayre PH, Plaut M, Bahnson HT, Mitchell H, Radulovic S, Chan S, Fox A, Turcanu V, Lack G. (2011) Identifying infants at high risk of peanut allergy: The Learning Early About Peanut Allergy (LEAP) screening studyJ Allergy Clin Immunol, 131(1), 135-143. DOI: PMID: 23174658 PMCID: [PubMed] [Reprint]
Sicherer SH, Sampson HA. (2016) Food Allergy: A review and update on epidemiology, pathogenesis, diagnosis, prevention and managementJ Allergy Clin Immunol, (), . DOI: 10.1016/j.jaci.2017.11.003 PMID: 29157945 PMCID: [PubMed] [Reprint]
Greenhawt M, Fleischer DM, Chan ES, Venter C, Stukus D, Gupta R, Spergel JM. (2016) LEAPing through the looking glass: secondary analysis of the effect of skin test size and age of introduction on peanut tolerance after early peanut introductionAllergy, 72(8), 1254-60. DOI: 10.1111/all.13100 PMID: 27896827 PMCID: PMC5447487 [PubMed] [Reprint]
Feeney M, Du Toit G, Roberts G, Sayre PH, Lawson K, Bahnson HT, Sever ML, Radulovic S, Plaut M, Lack G, Immune Tolerance Network LEAP Study Team. (2015) Impact of peanut consumption in the LEAP Study: Feasibility, growth, and nutrition J Allergy Clin Immunol, pii: S0091-6749(16), 30262-7. DOI: 10.1016/j.jaci.2016.04.016 PMID: 27297994 PMCID: PMC5056823 [PubMed] [Reprint]
Du Toit G, Roberts G, Sayre P, Turcanu V, Fisher HR, Broide D, Nirenstein L, Radulovic S, Stephens A, Seyfert-Margolis V, Nasser N, Murphy S, The Immune Tolerance Network ITN032AD Study Group, Lack G. Induction Of Tolerance Through Early Introduction Of Peanut In High-Risk Children, The LEAP Study. (Abstract #84) 2010 AAAAI Annual Meeting, New Orleans, LA, February 26 - March 2, 2010.
Roberts G, Du Toit G, Sayre P, Turcanu V, Fisher HR, Broide D, Nirenstein L, Radulovic S, Stephens A, Seyfert-Margolis V, Nasser N, Murphy S, The Immune Tolerance Network ITN032AD Study Group, Lack G. Infants with Eczema have High Rates of Sensitization to Food Allergens - results from the Leap Study. (Abstract #363) 2010 AAAAI Annual Meeting, New Orleans, LA, February 26 - March 2, 2010.
Lawson K, Bahnson HT, Sever M, Du Toit G, Lack G, Brittain E, Keet C, Greenhawt M, Fleischer D, Chan ES, Venter C, Stukus D, Gupta R, Spergel J. (2016) Letter of response to Greenhawt et al. 'LEAPing Through the Looking Glass: Secondary Analysis of the Effect of Skin Test Size and Age of Introduction on Peanut Tolerance after Early Peanut Introduction'Allergy, 72(8), 1267-71. DOI: 10.1111/all.13127 PMID: 28691223 PMCID: [PubMed]