Recent Findings in Food Allergy Research By Emily Brock, Nadeau Laboratory January 2013 In recent years, allergic disorders have reached epidemic proportions in children and adults. Today, 1 in every 13 children suffers from food allergies with nearly 12 million Americans affected across the country. As food allergies continue to increase in prevalence, research centers are working together to achieve what seems like an impossible dream: a cure. Until recently, the only solution for food allergies was strict avoidance of the allergen. Now, scientists and physicians at Lucile Packard Children’s Hospital, Stanford University of Medicine, and other centers around the world are developing groundbreaking treatments that push beyond the traditional protocol of strict avoidance. In this article, the Stanford Alliance for Food Allergy Research (SAFAR) shares with you recent developments in a growing area of research: immunotherapies aimed at inducing desensitization and tolerance to food allergens. The practice of immunotherapy involves gradually exposing patients to an allergen until their immune system is able to tolerate the substance. Since even small traces of an allergen carry the risk of anaphylaxis, this therapy is only administered under the supervision of trained medical personnel and should never be attempted under different circumstances. This article highlights research in the areas of oral immunotherapy (OIT)—a treatment characterized by eating or drinking incrementally small doses of a food allergen over time in order to induce desensitization, and sublingual immunotherapy (SLIT)—a therapy in which an allergen solution is dissolved under a patient’s tongue. Additionally, you’ll find out more about a relatively new form of therapy called anti-‐IgE therapy. When used in conjunction with OIT, the use of an anti-‐IgE drug such as Omalizumab has shown to increase the rate of achieving desensitization. We also hope to elucidate the immunologic changes that occur during the process of desensitization. Working in collaboration with a broad network of scientists and physicians around the country, SAFAR is currently the only center on the West Coast conducting oral immunotherapy trials (OIT). It is the only center in the United States to offer clinical research trials to patients with multiple food allergies. Oral Immunotherapy results are promising The results of oral immunotherapy studies are promising. Patients who have undergone oral immunotherapy have been consistently desensitized to allergens such as cow’s milk, egg white, and peanut. In a group of extensively reviewed studies123456789, desensitization was achieved in 50% to 75% of trial participants. Additionally, a meta-‐analysis10 conducted in 2011 found that patients undergoing OIT for milk were 10 times more likely to develop tolerance than patients on an elimination diet. More recently, an OIT study11 published in July 2012 showed that of 55 egg-‐allergic children who underwent OIT, 30 children (75%) achieved desensitization at 22 months. Following a 4-‐6 week period of OIT discontinuation and egg avoidance, 11 of these children (28%) showed sustained desensitization to egg, a subset considered clinically significant. © 2013 Stanford School of Medicine While there are many different protocols for OIT, they generally follow a similar course: a low starting dosage of the allergen (usually administered as a protein powder mixed with a safe vehicle), an increase in dosage every 2-‐4 weeks, and a maximum dosage that is high enough to protect patients from accidental exposure. In the United States, OIT often begins with a build up phase to get patients up to a minimum dosage. This phase is then followed by a dose escalation at fixed intervals. It is worth noting that patients who achieve desensitization through OIT appear to require regular exposure to the allergen in order to maintain tolerance. In comparison, reoccurrence to an allergy is rare if tolerance is developed naturally. In light of this, patients with a peanut allergy should only undergo OIT if they are likely to consume the allergen on a regular basis. After desensitization has been achieved, patients should continue to carry self-‐injectable epinephrine at all times since long-‐term results continue to be evaluated. IN DEPTH: SUMMARY OF RECENT OIT STUDIES Oral Immunotherapy for treatment of egg allergy in children (Burks AW, Jones SM, Wood RA, et al, N Engl J Med 2012;367(3):233-‐43) In this double-‐blind, placebo-‐controlled (DBPCFC) study published in July 2012, 55 children with an egg allergy received either OIT to egg white (40 children) or a placebo (15 children). OIT consisted of a rush phase, a long-‐term buildup phase, and a maintenance phase. These phases were followed by an OFC with egg white powder at 10 and 22 months. At 10 months, 55% of the OIT subjects passed the OFC and were considered desensitized to egg. In comparison, none of the placebo group passed the OFC. At 22 months, 75% of the OIT patients were desensitized. These patients proceeded to discontinue OIT and avoid all egg consumption for 4 to 6 weeks. At 24 months, 28% of these children passed the OFC and were considered to have sustained desensitization to egg. These children were then placed on an unrestricted diet and evaluated at 30 and 36 months. At 30 months and 36 months, all the children who had passed the OFC at 24 months were consuming egg. Allergy to goat’s and sheep’s milk in a population of cow’s milk–allergic children treated with oral immunotherapy (Rodríguez del Rio P, Sanchez-‐Garcia S, Escudero C, et al, Pediatr Allergy Immunol 2012;23(2):128-‐32) In a recent 2012 study, patients who successfully underwent OIT for cow’s milk (CM) were tested for allergies to goat and sheep’s milk (GSM). A high prevalence (25.9%) of these patients also had GSM allergies as confirmed by a positive OFC. CM-‐allergic patients who successfully underwent OIT tolerated a higher dose of GSM than CM-‐ allergic patients who had not undergone OIT. However, most patients had moderate to severe reactions, with 47% suffering from anaphylaxis. The study shows that OIT for CM is not sufficient to treat other milk allergies and recommends assessing tolerance to GSM in CM-‐allergic patients to provide accurate nutritional advice and minimize life-‐threatening reactions resulting from accidental intake. Anti-‐IgE Therapy increases rate of desensitization A fairly recent development in allergy research is the use of anti-‐IgE therapy in conjunction with OIT. Anti-‐IgE drugs such as Omalizumab and Talizumab, have been shown to significantly increase the rate of reaching desensitization during OIT. Anti-‐IgE antibodies work by blocking IgE binding epitopes as well as decreasing FCεRI expression. Additionally, anti-‐IgE antibodies may also decrease the production of TH2 cytokines—protein molecules that trigger IgE production. © 2013 Stanford School of Medicine In a recent study by Dr. Nadeau12 (research lead of the Stanford Alliance for Food Allergy Research), treatment with anti-‐IgE therapy prior to and during OIT vastly increased patients’ rate of reaching their maintenance dose. Specifically, patients reached their maintenance dose in 7 weeks to a few months, with 9 of the 11 patients attaining full desensitization during the course of the trial. In comparison, patients participating in trials without anti-‐IgE treatment, typically achieve desensitization within a 1-‐3 year time period. Sublingual immunotherapy has fewer adverse effects than OIT but is less effective Sublingual immunotherapy (SLIT)—a treatment characterized by placing the allergen under the subject’s tongue—has also been used to desensitize patients with food allergies. When compared to OIT, SLIT has fewer adverse effects than OIT. However, it is less effective than OIT in desensitization and induction of tolerance. This is likely due to common dose limits in SLIT. The maximum reasonable allergen dosage in SLIT is 700mg, whereas OIT can have dosages at least as high as 5000mg. IN DEPTH: SUMMARY OF RECENT SUBLINGUAL IMMUNOTHERAPY STUDY The safety and efficacy of sublingual and oral immunotherapy for milk allergy (Keet CA, Frischmeyer-‐ Guerrerio PA, Thyagarajan A, et al, J Allergy Clin Immunol 2012;129(2)448-‐55, 455.e1-‐5.) This recent study compared the efficacy and safety of SLIT and OIT. In this study, 30 subjects began SLIT for a milk allergy. After six weeks patients were split into three groups: one group continued SLIT with the goal of a maintenance dose of 7mg, another began OIT with a goal of a maintenance dose of 2g, the third began OIT with a goal of a maintenance dose of 1g. After 48 weeks on a maintenance dose, subjects underwent an OFC. If successful, therapy was discontinued and an OFC was repeated one week later. If the subject passed, then another OFC was performed 5 weeks later. This study found that SLIT was less effective than OIT in inducing full desensitization, with only 1 in 10 SLIT subjects passing the OFC after 48 weeks of maintenance therapy. In comparison, 7 of the 10 OIT patients on the 1 g maintenance dose and 9 of the 10 OIT patients on the 2 g maintenance dose achieved desensitization. After discontinuing the therapy for six weeks, 8 of the OIT patients and 1 of the SLIT patients were considered tolerant. In conclusion, OIT appears to be more successful in inducing desensitization to milk in patients as compared to SLIT, however OIT was accompanied by more frequent serious adverse effects. The immunologic changes of desensitization More is being learned every day about the immunologic changes that occur during allergic reactions and desensitization. Many studies show that gradual exposure to an allergen results in the following immunologic changes: a decreased weal size from a skin prick test (SPT), a decrease in immunoglobulin E (IgE) antibodies, and an increase in IgG4—a subclass of immunoglobulin G (IgG) antibodies. You may already know that IgE antibodies respond to foreign substances like allergens by triggering the release of histamines into the body, causing inflammation. IgG4 antibodies compete with IgE antibodies for allergen binding and help prevent the release of histamine. T cells play a role Many studies have determined that the immune system of patients with allergies is overactive and skewed toward a certain subtype of immune cell called the Th2 cell. Th2 cells produce cytokines— © 2013 Stanford School of Medicine signaling protein molecules – that mediate IgE production. Studies by Blumchen et al8 and Varshney et al9 have found that desensitization results in the decrease of TH2 cytokine production. Additionally, an OIT study by Fuentes-‐Aparicio et al13 suggests that a specific T cell subset may be decreased in allergic patients but that over the course of desensitization is increased to normal levels. This subset of T cells may be a marker of the development of oral tolerance. The Nadeau Laboratory (SAFAR’s scientific team) has found that a type of cell called natural regulatory T cells can decrease the over-‐activation of Th2 cells in allergies, which can lead to reduced—or even reversed—allergic conditions. By understanding how these regulatory T cells work, researchers at the Nadeau Laboratory hope to discover new diagnostic and therapeutic methods of treating or preventing allergic conditions. Continued support fuels critical SAFAR research The Stanford Alliance for Food Allergy Research (SAFAR) continues to work collaboratively with allergy specialists and researchers in the medical community to develop new and safe treatments for food allergies. While more is being learned about the immunologic changes that occur during desensitization, very little is understood about the mechanisms of inducing tolerance. Advancements in food allergy research are progressing as quickly as resources allow. With your help, we can work together as a community to achieve a possible cure. To learn more about SAFAR’s clinical studies, please visit http://foodallergies.stanford.edu/trial/. 1 Meglio P, Bartone E, Plantamura M, et al. A protocol for oral desensitization in children with IgE-‐mediated cow’s milk allergy. Allergy 2004;59:980–7. 2 Buchanan AD, Green TD, Jones SM, et al. Egg oral immunotherapy in nonanaphylactic children with egg allergy. J Allergy Clin Immunol 2007;119(1):199–205. 3 Staden U, Rolinck-‐Werninghaus C, Brewe F, et al. Specific oral tolerance induction in food allergy in children: efficacy and clinical patterns of reaction. Allergy 2007;62:1261–9. 4 Longo G, Barbi E, Berti I, et al. Specific oral tolerance induction in children with very severe cow’s milk-‐induced reactions. J Allergy Clin Immunol 2008;121(2):343–7. 5 Skripak JM, Nash SD, Rowley H, et al. A randomized, double-‐blind, placebo-‐controlled study of milk oral immunotherapy for cow’s milk allergy. J Allergy Clin Immunol 2008;122(6):1154–60. 6 Clark AT, Islam S, King Y, et al. Successful oral tolerance induction in severe peanut allergy. Allergy 2009;64(8):1218–20. 7 Jones SM, Pons L, Roberts JL, et al. Clinical efficacy and immune regulation with peanut oral immunotherapy. J Allergy Clin Immunol 2009;124(2):292–300, 300.e1–97. 8 Blumchen K, Ulbricht H, Staden U, et al. Oral peanut immunotherapy in children with peanut anaphylaxis. J Allergy Clin Immunol 2010;126(1):83-‐91.e1. 9 Varshney P, Jones SM, Scurlock AM, et al. A randomized controlled study of peanut oral immunotherapy: clinical desensitization and modulation of the allergic response. J Allergy Clin Immunol 2011;127(3):654-‐60. 10 Brozek JL, Terracciano L, Hsu J, et al. Oral immunotherapy for IgE-‐mediate cow’s milk allergy: a systematic review and meta-‐analysis. Clin Exp Allergy 2012;42(3):363-‐74. 11 Burks AW, Jones SM, Wood RA, et al. Oral immunotherapy for treatment of egg allergy in children. N Engl J Med 2012;367(3):233-‐43. 12 Nadeau KC, Schneider LC, Hoyte L, et al. Rapid oral desensitization in combination with omalizumab therapy in patients with cow’s milk allergy. J Allergy Clin Immunol 2011;127(6):1622-‐4. 13 Fuentes-‐Aparicio V, Alonso-‐Lebrero E, Zapatero L, et al. Oral immunotherapy in hen’s egg-‐allergic children increases a hypo-‐proliferative subset of CD4+ T cells that could constitute a marker of tolerance achievement. Pediatr Allergy Immunol 2012 Jul 26. © 2013 Stanford School of Medicine