Novel Immunotherapy Approaches to Food Allergy

Abstract and Introduction

Abstract

Purpose of review Despite reaching high percentages of desensitization using allergen-specific immunotherapy (SIT) in patients with food allergy, recent studies suggest only a low number of patients to reach persistent clinical tolerance. This review describes current developments in strategies to improve safety and long-term efficacy of SIT.

Recent findings Modified allergens or tolerogenic peptides, ultimately optimized for human leukocyte antigen background of the patient, are explored for tolerance induction, whereas anti-IgE antibody (Omalizumab) may be used to facilitate SIT safety. Adjunct therapies to enhance efficacy may make use of T_H1 polarizing agents, for example, CpG-oligodeoxynucleotides combined with modified allergen packaged in nanoparticles. Preclinical studies showed insulin-like growth factor-2, intravenous immunoglobulin, Tregitopes or allergen encased oligomannose-coated liposomes capable of inducing regulatory T-cells, recognized for their importance in clinical tolerance induction. Dietary intervention strategies utilizing herbal formula 2, VSL#3, nondigestible short-chain galacto-oligosaccharides and long-chain fructo-oligosaccharides (scGOS/lcFOS) plus Bifidobacterium breve M-16V or n-3 long-chain polyunsaturated fatty acids may facilitate safety and/or a favourable milieu for tolerance induction.

Summary Combining SIT using (adapted) allergens or tolerogenic peptides with adjunct therapy may be essential to improve safety and/or efficacy. Beyond using targeted approaches, specific dietary components may be explored to reduce side-effects and support clinical tolerance induction by SIT.

Introduction

The rising prevalence of allergic diseases relates to the increase in noncommunicable diseases, and food allergy may be seen as an early onset noncommunicable disease.^[1] Food allergy is one of the first manifestations of atopic constitution and affects 6% of children and 3 to 4% of adults in westernized countries. Cow's milk and hen's egg are the main contributors to early childhood allergy and are outgrown in 80% of patients, by contrast, peanut allergy is resolving in less than 20%. Intake of the culprit food results in local (oropharyngeal/gastrointestinal) and/or systemic (atopic dermatitis, asthma) symptoms, ranging from mild (itching) to extremely severe (anaphylactic shock). Food allergen-specific immunotherapy (SIT) is being explored, but safety and long-term efficacy issues currently question its applicability for general clinical practice.^[2,3] This review provides an update on clinical trials published over the last year using SIT in IgE-mediated cow's milk, hen's egg and peanut allergy. Furthermore, novel developments in allergen modification and adjunct therapies to improve safety and (long-term) efficacy are discussed.

Table 1. Summary of recent clinical trials for oral immunotherapy, sublingual immunotherapy and epicutaneous immunotherapy
Reference	Allergen/therapy	Number of patients	Desensitization/tolerance	Immunological changes	Safety
Anagnostou 2014	Peanut; OIT	85 (ages 7–16) Placebo: 46; OIT: 39	Desensitization; Full: 62%; Partial: 22%; Increased median threshold 25-fold	Not investigated	Epinephrine given to one patient subject. 19% β2-agonist
Chin 2013	Peanut; OIT/SLIT	50 (ages 2–11) OIT: 23; SLIT: 27	OIT three times more likely to pass DBPCFC at 12 months. Variable and lower eliciting dose thresholds by SLIT	OIT larger changes in peanut IgE and IgG4 levels than SLIT	Four doses epinephrine for two patients in OIT
Fleischer 2013	Peanut; SLIT	40 (age 12–37) Placebo: 20; SLIT: 20	Desensitization SLIT: 70%Placebo: 15%	Increase allergen-specific IgG4 for SLIT patients. No difference responders and nonresponders	Dose-related oral-pharyngeal symptoms; One dose epinephrine
Syed 2014	Peanut; OIT	43 (ages 4–55) OIT: 23; Abstaining peanut: 20	Desensitization; OIT: 87%; Lasting tolerance: 13%	Immune-tolerant patients higher antigen-induced Tregs. IgG4 no predictor of lasting tolerance	Not assessed
Vickery 2014	Peanut; OIT	39 (ages 1–16)	Sustained unresponsiveness: 31% (1 month after OIT)	Sustained unresponsiveness correlated with lower baseline IgE levels. No role for IgG4	15% withdrawal allergic side-effects
Dello Iacono 2013	Hen's egg; OIT	20 (5-11 years) OIT: 10; Placebo: 10	Desensitization; Partial: 90% (median 20 ml)	Increase threshold not correlated with level serum-specific IgE	Adverse effects in all subjectspatients, dose-related. 66% grade III, 9% grade IV
Meglio 2013	Hen's egg; OIT	20 (age ≥years)	Desensitization; Full: 80% (25 mL); Partial:10%	IgG4 levels for ovalbumin increased significantly	30% reached full dose symptom free
Keet 2013	Cow's milk; OIT	32 Follow-up from two studies	Follow-up study, 31% full serving with minimal or no symptoms	Baseline IgE important for outcome	19% at least one anaphylaxis, 9% at least one dose of epinephrine
Vázquez-Ortiz 2013	Cow's milk; OIT	81 (age 5–18)	Desensitization; Full: 72% (200 ml); Partial: 21%	Baseline IgE important for outcome	14 patients persistent reactions; six adverse effects