Investigational therapies for food allergy: SLIT, EPIT, SCIT, and nonspecific therapies
- Anna Nowak-Węgrzyn, MD
Anna Nowak-Węgrzyn, MD
- Associate Professor of Pediatrics
- Icahn School of Medicine at Mount Sinai
Food allergy encompasses a variety of immune-mediated adverse reactions to foods that occur in genetically predisposed individuals [1,2]. Management of food allergy consists of strict avoidance of the food allergen and treatment of accidental exposures with medications. Allergies to certain foods, such as egg and milk, tend to be outgrown during childhood, whereas allergies to other foods, such as shellfish and nuts, are much more likely to persist. Several approaches are under investigation for the treatment of food allergy. (See "Management of food allergy: Avoidance" and "Food-induced anaphylaxis" and "Anaphylaxis: Emergency treatment".)
Novel therapeutic approaches to food allergy can be classified as food allergen specific (eg, immunotherapy with native or modified recombinant allergens, or oral desensitization) or food allergen nonspecific (eg, anti-immunoglobulin E [IgE], traditional Chinese medicine [TCM]) (table 1) [3-6]. The goal of these therapies is to induce permanent tolerance to the food, where the allergy will not recur upon re-exposure after a period of abstinence. However, some therapies in development appear to only temporarily desensitize or protect patients, requiring continued treatment to maintain efficacy. Before these new approaches are applied in clinical practice, they must be carefully evaluated for side effects, such as acute adverse reactions, toxicity, and overstimulation of T helper type 1 (Th1) immune responses that could prime for autoimmunity.
Oral immunotherapy (OIT) for food allergy is reviewed separately. Other food-specific therapies, as well as nonspecific therapies, are reviewed here. (See "Investigational therapies for food allergy: Oral immunotherapy".)
FOOD ALLERGEN-SPECIFIC THERAPY
The aim of allergen-specific therapies is to alter the allergic response to the food allergen so that the patient becomes desensitized or, preferably, tolerant to the specific food. Possible future food allergen-specific therapies include oral, sublingual, and subcutaneous immunotherapy. Allergens used for subcutaneous immunotherapy have been modified to retain immunogenicity but decrease allergenicity.
Sublingual immunotherapy — Another approach to food immunotherapy is sublingual immunotherapy (SLIT) with food extracts. There are few effector cells, such as mast cells, in the sublingual mucosa . Allergen extracts given sublingually are not systemically absorbed. Rather, they are taken up by dendritic cells in the mucosa and presented to T cells in the draining lymph nodes. Likely mechanisms of action include downregulation of mast cells and activation of T regulatory cells. SLIT has been attempted for peanut, hazelnut, cow's milk (CM), and kiwi allergies.To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Sampson HA. Update on food allergy. J Allergy Clin Immunol 2004; 113:805.
- Boyce JA, Assa'ad A, Burks AW, et al. Guidelines for the Diagnosis and Management of Food Allergy in the United States: Summary of the NIAID-Sponsored Expert Panel Report. J Allergy Clin Immunol 2010; 126:1105.
- Sicherer SH, Leung DY. Advances in allergic skin disease, anaphylaxis, and hypersensitivity reactions to foods, drugs, and insects in 2007. J Allergy Clin Immunol 2008; 121:1351.
- Eigenmann PA, Beyer K, Wesley Burks A, et al. New visions for food allergy: an iPAC summary and future trends. Pediatr Allergy Immunol 2008; 19 Suppl 19:26.
- Sicherer SH, Sampson HA. Food allergy: recent advances in pathophysiology and treatment. Annu Rev Med 2009; 60:261.
- Nowak-Węgrzyn A, Sampson HA. Future therapies for food allergies. J Allergy Clin Immunol 2011; 127:558.
- Frati F, Moingeon P, Marcucci F, et al. Mucosal immunization application to allergic disease: sublingual immunotherapy. Allergy Asthma Proc 2007; 28:35.
- Enrique E, Pineda F, Malek T, et al. Sublingual immunotherapy for hazelnut food allergy: a randomized, double-blind, placebo-controlled study with a standardized hazelnut extract. J Allergy Clin Immunol 2005; 116:1073.
- Mempel M, Rakoski J, Ring J, Ollert M. Severe anaphylaxis to kiwi fruit: Immunologic changes related to successful sublingual allergen immunotherapy. J Allergy Clin Immunol 2003; 111:1406.
- Keet CA, Frischmeyer-Guerrerio PA, Thyagarajan A, et al. The safety and efficacy of sublingual and oral immunotherapy for milk allergy. J Allergy Clin Immunol 2012; 129:448.
- Kim EH, Bird JA, Kulis M, et al. Sublingual immunotherapy for peanut allergy: clinical and immunologic evidence of desensitization. J Allergy Clin Immunol 2011; 127:640.
- Narisety SD, Frischmeyer-Guerrerio PA, Keet CA, et al. A randomized, double-blind, placebo-controlled pilot study of sublingual versus oral immunotherapy for the treatment of peanut allergy. J Allergy Clin Immunol 2015; 135:1275.
- Enrique E, Malek T, Pineda F, et al. Sublingual immunotherapy for hazelnut food allergy: a follow-up study. Ann Allergy Asthma Immunol 2008; 100:283.
- Fleischer DM, Burks AW, Vickery BP, et al. Sublingual immunotherapy for peanut allergy: a randomized, double-blind, placebo-controlled multicenter trial. J Allergy Clin Immunol 2013; 131:119.
- Burks AW, Wood RA, Jones SM, et al. Sublingual immunotherapy for peanut allergy: Long-term follow-up of a randomized multicenter trial. J Allergy Clin Immunol 2015; 135:1240.
- Kerzl R, Simonowa A, Ring J, et al. Life-threatening anaphylaxis to kiwi fruit: protective sublingual allergen immunotherapy effect persists even after discontinuation. J Allergy Clin Immunol 2007; 119:507.
- de Boissieu D, Dupont C. Sublingual immunotherapy for cow's milk protein allergy: a preliminary report. Allergy 2006; 61:1238.
- Mondoulet L, Dioszeghy V, Ligouis M, et al. Epicutaneous immunotherapy on intact skin using a new delivery system in a murine model of allergy. Clin Exp Allergy 2010; 40:659.
- Strid J, Hourihane J, Kimber I, et al. Epicutaneous exposure to peanut protein prevents oral tolerance and enhances allergic sensitization. Clin Exp Allergy 2005; 35:757.
- Oyoshi MK, Elkhal A, Scott JE, et al. Epicutaneous challenge of orally immunized mice redirects antigen-specific gut-homing T cells to the skin. J Clin Invest 2011; 121:2210.
- Mondoulet L, Dioszeghy V, Puteaux E, et al. Intact skin and not stripped skin is crucial for the safety and efficacy of peanut epicutaneous immunotherapy (EPIT) in mice. Clin Transl Allergy 2012; 2:22.
- Mondoulet L, Dioszeghy V, Larcher T, et al. Epicutaneous immunotherapy (EPIT) blocks the allergic esophago-gastro-enteropathy induced by sustained oral exposure to peanuts in sensitized mice. PLoS One 2012; 7:e31967.
- Dupont C, Kalach N, Soulaines P, et al. Cow's milk epicutaneous immunotherapy in children: a pilot trial of safety, acceptability, and impact on allergic reactivity. J Allergy Clin Immunol 2010; 125:1165.
- Jones SM, Agbotounou WK, Fleischer DM, et al. Safety of epicutaneous immunotherapy for the treatment of peanut allergy: A phase 1 study using the Viaskin patch. J Allergy Clin Immunol 2016; 137:1258.
- Sampson HA, Agbotounou W, Thebault C, et al. Epicutaneous Immunotherapy (EPIT) Is Effective and Safe to Treat Peanut Allergy: A Multi-National Double-Blind Placebo-Controlled Randomized Phase IIb Trial. J Allergy Clin Immunol 2015; 135:AB390.
- Jones SM, Sicherer SH, Burks AW, et al. Epicutaneous immunotherapy for the treatment of peanut allergy in children and young adults. J Allergy Clin Immunol 2017; 139:1242.
- Oppenheimer JJ, Nelson HS, Bock SA, et al. Treatment of peanut allergy with rush immunotherapy. J Allergy Clin Immunol 1992; 90:256.
- Nelson HS, Lahr J, Rule R, et al. Treatment of anaphylactic sensitivity to peanuts by immunotherapy with injections of aqueous peanut extract. J Allergy Clin Immunol 1997; 99:744.
- Briner TJ, Kuo MC, Keating KM, et al. Peripheral T-cell tolerance induced in naive and primed mice by subcutaneous injection of peptides from the major cat allergen Fel d I. Proc Natl Acad Sci U S A 1993; 90:7608.
- Hong SJ, Michael JG, Fehringer A, Leung DY. Pepsin-digested peanut contains T-cell epitopes but no IgE epitopes. J Allergy Clin Immunol 1999; 104:473.
- Li S, Li XM, Burks AW, Sampson HA. Modulation of peanut allergy by peptide-based immunotherapy. J Allergy Clin Immunol 2001; 107:S233 (Abstract).
- Prickett SR, Voskamp AL, Dacumos-Hill A, et al. Ara h 2 peptides containing dominant CD4+ T-cell epitopes: candidates for a peanut allergy therapeutic. J Allergy Clin Immunol 2011; 127:608.
- Valenta R, Vrtala S, Laffer S, et al. Recombinant allergens. Allergy 1998; 53:552.
- Li X, Huang CK, Schofield BH, et al. Strain-dependent induction of allergic sensitization caused by peanut allergen DNA immunization in mice. J Immunol 1999; 162:3045.
- Nowak-Wegrzyn A. New perspectives for use of native and engineered recombinant food proteins in treatment of food allergy. Immunol Allergy Clin North Am 2007; 27:105.
- Burks AW, Cockrell G, Stanley JS, et al. Recombinant peanut allergen Ara h I expression and IgE binding in patients with peanut hypersensitivity. J Clin Invest 1995; 96:1715.
- Eigenmann PA, Burks AW, Bannon GA, Sampson HA. Identification of unique peanut and soy allergens in sera adsorbed with cross-reacting antibodies. J Allergy Clin Immunol 1996; 98:969.
- Stanley JS, King N, Burks AW, et al. Identification and mutational analysis of the immunodominant IgE binding epitopes of the major peanut allergen Ara h 2. Arch Biochem Biophys 1997; 342:244.
- Rabjohn P, Helm EM, Stanley JS, et al. Molecular cloning and epitope analysis of the peanut allergen Ara h 3. J Clin Invest 1999; 103:535.
- Bannon GA, Cockrell G, Connaughton C, et al. Engineering, characterization and in vitro efficacy of the major peanut allergens for use in immunotherapy. Int Arch Allergy Immunol 2001; 124:70.
- Srivastava KD, Li XM, King N, et al. Immunotherapy with modified peanut allergens in a murine model of peanut allergy. J Allergy Clin Immunol 2002; 109:S287 (Abstract).
- Wood RA, Sicherer SH, Burks AW, et al. A phase 1 study of heat/phenol-killed, E. coli-encapsulated, recombinant modified peanut proteins Ara h 1, Ara h 2, and Ara h 3 (EMP-123) for the treatment of peanut allergy. Allergy 2013; 68:803.
- Swoboda I, Bugajska-Schretter A, Linhart B, et al. A recombinant hypoallergenic parvalbumin mutant for immunotherapy of IgE-mediated fish allergy. J Immunol 2007; 178:6290.
- Yeung VP, Gieni RS, Umetsu DT, DeKruyff RH. Heat-killed Listeria monocytogenes as an adjuvant converts established murine Th2-dominated immune responses into Th1-dominated responses. J Immunol 1998; 161:4146.
- Frick OL, Teuber SS, Buchanan BB, et al. Allergen immunotherapy with heat-killed Listeria monocytogenes alleviates peanut and food-induced anaphylaxis in dogs. Allergy 2005; 60:243.
- Li XM, Srivastava K, Huleatt JW, et al. Engineered recombinant peanut protein and heat-killed Listeria monocytogenes coadministration protects against peanut-induced anaphylaxis in a murine model. J Immunol 2003; 170:3289.
- Stanley JS, Buzen F, Cockrell G, et al. Immunotherapy for peanut allergy using modified allergens and a bacterial adjuvant. J Allergy Clin Immunol 2002; 109:S93 (Abstract).
- Li XM, Srivastava K, Grishin A, et al. Persistent protective effect of heat-killed Escherichia coli producing "engineered," recombinant peanut proteins in a murine model of peanut allergy. J Allergy Clin Immunol 2003; 112:159.
- Srivastava K, Li XM, Bannon GA, et al. Investigation of the use of ISS-linked Ara h2 for the treatment of peanut-induced allergy. J Allergy Clin Immunol 2001; 107:S233 (Abstract).
- Nguyen MD, Cinman N, Yen J, Horner AA. DNA-based vaccination for the treatment of food allergy. Allergy 2001; 56 Suppl 67:127.
- Zhang K, Kepley CL, Terada T, et al. Inhibition of allergen-specific IgE reactivity by a human Ig Fcgamma-Fcepsilon bifunctional fusion protein. J Allergy Clin Immunol 2004; 114:321.
- Kepley CL, Taghavi S, Mackay G, et al. Co-aggregation of FcgammaRII with FcepsilonRI on human mast cells inhibits antigen-induced secretion and involves SHIP-Grb2-Dok complexes. J Biol Chem 2004; 279:35139.
- Zhang K, Zhu D, Kepley C, et al. Chimeric human fcgamma-allergen fusion proteins in the prevention of allergy. Immunol Allergy Clin North Am 2007; 27:93.
- Zhou Y, Kawasaki H, Hsu SC, et al. Oral tolerance to food-induced systemic anaphylaxis mediated by the C-type lectin SIGNR1. Nat Med 2010; 16:1128.
- Cortes-Perez NG, Ah-Leung S, Bermúdez-Humarán LG, et al. Intranasal coadministration of live lactococci producing interleukin-12 and a major cow's milk allergen inhibits allergic reaction in mice. Clin Vaccine Immunol 2007; 14:226.
- Cortes-Perez NG, Ah-Leung S, Bermúdez-Humarán LG, et al. Allergy therapy by intranasal administration with recombinant Lactococcus lactis Producing bovine beta-lactoglobulin. Int Arch Allergy Immunol 2009; 150:25.
- Straumann A, Conus S, Grzonka P, et al. Anti-interleukin-5 antibody treatment (mepolizumab) in active eosinophilic oesophagitis: a randomised, placebo-controlled, double-blind trial. Gut 2010; 59:21.
- Summers RW, Elliott DE, Urban JF Jr, et al. Trichuris suis therapy for active ulcerative colitis: a randomized controlled trial. Gastroenterology 2005; 128:825.
- Summers RW, Elliott DE, Urban JF Jr, et al. Trichuris suis therapy in Crohn's disease. Gut 2005; 54:87.
- Zhu FG, Kandimalla ER, Yu D, Agrawal S. Oral administration of a synthetic agonist of Toll-like receptor 9 potently modulates peanut-induced allergy in mice. J Allergy Clin Immunol 2007; 120:631.
- Fahy JV, Fleming HE, Wong HH, et al. The effect of an anti-IgE monoclonal antibody on the early- and late-phase responses to allergen inhalation in asthmatic subjects. Am J Respir Crit Care Med 1997; 155:1828.
- MacGlashan DW Jr, Bochner BS, Adelman DC, et al. Down-regulation of Fc(epsilon)RI expression on human basophils during in vivo treatment of atopic patients with anti-IgE antibody. J Immunol 1997; 158:1438.
- Leung DY, Sampson HA, Yunginger JW, et al. Effect of anti-IgE therapy in patients with peanut allergy. N Engl J Med 2003; 348:986.
- Kattan JD, Srivastava KD, Zou ZM, et al. Pharmacological and immunological effects of individual herbs in the Food Allergy Herbal Formula-2 (FAHF-2) on peanut allergy. Phytother Res 2008; 22:651.
- Dahdah L, Ceccarelli S, Amendola S, et al. IgE Immunoadsorption Knocks Down the Risk of Food-Related Anaphylaxis. Pediatrics 2015; 136:e1617.
- Bielory L, Lupoli K. Herbal interventions in asthma and allergy. J Asthma 1999; 36:1.
- Ziment I, Tashkin DP. Alternative medicine for allergy and asthma. J Allergy Clin Immunol 2000; 106:603.
- Arias K, Baig M, Colangelo M, et al. Concurrent blockade of platelet-activating factor and histamine prevents life-threatening peanut-induced anaphylactic reactions. J Allergy Clin Immunol 2009; 124:307.
- FOOD ALLERGEN-SPECIFIC THERAPY
- Sublingual immunotherapy
- Epicutaneous immunotherapy
- Subcutaneous immunotherapy
- - Peptide immunotherapy
- - Engineered recombinant protein immunotherapy
- - Immunomodulatory adjuvants
- NONSPECIFIC THERAPY
- Humanized monoclonal anti-IgE
- Traditional Chinese medicine
- Blockade of vasoactive mediators
- Food allergen-specific therapy
- Nonspecific therapy