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Debates in Allergy Medicine: Does oral immunotherapyshorten the duration of milk and egg allergy?The pro argument

Debates in Allergy Medicine: Does oral immunotherapyshorten the duration of milk and egg... The development of oral tolerance or food allergy is an active process, related to dynamic interactions between host immune cells, microbiome, dietary factors, and food allergens. Oral tolerance is the default immune response in the gut. A food allergy occurs when this process fails and a pathologic Th2 response is activated. Oral food immunotherapy (OIT) aims to restore immune tolerance in food-allergic individuals. The stimulation of Tregs production seems to represent a crucial step in inducing long-term tolerance, but other mechanisms (e.g., the suppression of mast cell and basophil reactivity, changes in allergen-specific cells with regulatory markers) are involved. Several studies reported the efficacy of OIT in terms of "sustained unresponsiveness" (SU), an operational definition of immune tolerance. In successfully treated subjects, the ability to pass an oral food challenge 2 to 8 weeks after stopping the food allergen exposure seems to be conditioned by the treatment starting age, frequency, amount or type of food consumed, and by the duration of the maintenance phase. Based on the available data, the percentage of milk- and egg-allergic subjects achieving sustained unresponsiveness after an OIT ranges from 21% to 58,3%. A comprehensive understanding of mechanisms underlying the induction of oral tolerance with OIT, or natural tolerance to food allergens in healthy individuals, could potentially lead to advances in development of better treatment options for food allergic patients. Keywords: Cow’s milk, Desensitization, Hen’s egg, Oral immunotherapy, Oral tolerance, Sustained unresponsiveness Background Therefore, considering the increasing prevalence of food Despite increasing knowledge in oral tolerance, the allergy [10, 11] with a significant impact on the public current standard of care in treating food allergy accord- health in industrialized countries [12], attempts to mod- ing to the international guidelines is still a strict elimin- ify the immune response to foods are a required choice, ation diet [1–6]. However, the dietary approach has particularly in severe food allergies [13]. Oral immuno- several limitations. First, the risk for severe systemic re- therapy (OIT) aims to do so through food exposure. actions due to the presence of hidden allergens [7, 8]in The first report of successful desensitization per- food products in spite of best efforts at strictly avoiding formed in a hen’s egg allergic patient dates back to 1908 food allergens. Second, avoidance diets may be associ- [14], and until the end of the 1990s only a few sporadic ated to the risk of nutritional deficiencies and impaired cases were reported [15, 16]. The use of subcutaneous growth especially if the food/s involved represent route was related to high-risk of severe systemic reac- fundamental component of the conventional diet (such tions [17, 18] and was quickly abandoned. Starting from as cow’s milk or hen’s egg) [9]. Third, inadvertent the end of the twentieth Century, an increasing number exposure to food ingredients is an everyday risk. of OIT studies was reported in the literature. In addition to case reports [19, 20], clinical trials on OIT as an ef- fective treatment for food allergy began to be published * Correspondence: valentina.pecora@opbg.net Division of Allergy, IRCCS Ospedale Pediatrico Bambino Gesù, Piazza Sant’Onofrio, 4, 00165 Rome, Italy © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Pecora et al. World Allergy Organization Journal (2018) 11:11 Page 2 of 7 [21–24]. A hundred years after the first report, inter- T cell due to a functionally inactivation of lymphocyte national scientific societies became interested in OIT. following an antigen encounter, such as food or com- With the resulting exponential increase in the number mensal bacteria [34]. of clinical trials published, metanalyses became possible The intestinal microbiota varies between individuals, [25–29]. Their current evidence suggests a proved effi- and plays key roles in defense against pathogens as well cacy in short-term tolerance, while information on long- as food digestion and nutrition. In case of dietary term outcomes is limited and mostly focused on milk changes, a modification in bacterial metabolites (such as OIT. The long-term follow-up studies [30–33] have pro- short-chain fatty acids that derive from fermentation of posed to evaluate only the regular intake of the incrimi- dietary fibers) is observed, with repercussions on muco- nated food, sometimes reporting adverse reactions sal integrity and inflammasome activation [37]. The occurred during the follow-up period. Side effects com- inflammasome pathway and production of the cytokine monly reported in the literature are the main weakness interleukin (IL)-18 are critical for intestinal homeostasis of this treatment, which is still not recommended in the and epithelial integrity by ensuring repair and cell sur- routine clinical practice. Generally, most reactions aris- vival under stress conditions [38, 39]. ing from clinical trials are mild and limited to the oro- pharynx resolving without intervention or with Immunomodulation during a specific food allergen antihistamine alone. However, systemic or severe reac- immunotherapy tions do not seem unlikely and are most frequent during The goal of food immunotherapy (oral, sublingual or epi- the build-up phase commonly conducted under phys- cutaneous) is to modify the immune response towards ician supervision. food protein antigens. Many studies report suppression of mast cell and basophil reactivity, a reduction of allergen- Oral tolerance to food protein in the gut specific IgE and a simultaneous increase of allergen- The gastrointestinal tract is the major route of exposure specific IgG4 antibodies [40, 41]. At the same time, the to food allergens and the largest reservoir of immune cells interest of researchers was focused on Tregs, and specific- in the body. Intestinal commensal bacteria induce protect- ally on two different populations: CD4 + CD25+ forkhead ive and regulatory responses that maintain host-microbial box P3 (Foxp3) Treg cells and Th3 cells. The inhibitory mutualism, and the mucosal immune system plays a cru- cytokine TGF-β is responsible for the mechanism of sup- cial role protecting the gastrointestinal tract from invading pression provided by Th3 cells expressing a late-stage pathogens and keeping the commensal microbiota com- Treg activation marker, latency associated peptide (LAP), partmentalized. The epithelial cells, responsible for separ- which forms a complex with TGF-β [42, 43]. Based on the ating the mucosal immune system from the gut lumen, recent evidences [41], Foxp3+ Tregs were induced by the secrete a number of factors that contribute to barrier func- three treatment routes but in particular by epicutaneous reg tion, including mucins, antimicrobial peptides, and trefoil immunotherapy (EPIT). LAP+ T levels increase in EPIT factors. This type of cells also transport antibodies, par- and OIT, whereas IL-10 cells are induced by sublingual ticularly IgA, into the intestinal lumen where these anti- immunotherapy (SLIT). The suppressive activity of EPIT- regs bodies can contribute to barrier function by excluding the induced T required cytotoxic T-lymphocyte antigen 4 uptake of antigens or microbes [34]. The resident immune (CTLA-4), whereas SLIT is strictly dependent on IL-10 cells, located inside the matrix of the Peyer’spatches, in- and OIT acted through both mechanisms. IL-10 repre- + + clude CD4 and CD8 T effector and regulatory T cells sents a key cytokine inhibiting INF-γ and IL-2 secretion regs (T ), B cells, macrophages and dendritic cells. The latter by Th1 cells and IL-4/IL-5 production by Th2 cells. The reg in particular are critical for maintaining immune stimulation of T production seems to represent a homeostasis within the gut. Their major functions crucial step in inducing long-term tolerance. A boosting concern the processing and the presentation of antigens, a of antigen-specific serum IgA level was observed in a critical step in the activation of T cells. In detail, CD103 mouse model of food OIT [44]. In this case the dendritic cells in the mesenteric lymph nodes express high neutralization by allergen-specific IgA would demonstrate levels of the enzyme retinal dehydrogenase 2 (RALDH2), a protective role. In addition, according to the murine which converts retinal to retinoic acid promoting gut- model the OIT protection would be localized to the homing activity and development of Tregs from naïve T gastrointestinal tract with significant downregulation of cells as well as secretion of transforming growth factor β gastrointestinal gene expression [44]. (TGF-β)[35, 36]. Gut-associated intestinal lymphoid tissue discriminates Could OIT be conceived of as a disease-modifying between potentially harmful pathogens and non-harmful treatment? antigens. Therefore, it is possible to observe an activa- Until a few years ago, the possibility that OIT could be tion of a protective immune response or an ‘off ’ state of able to modify the natural history of food allergy was Pecora et al. World Allergy Organization Journal (2018) 11:11 Page 3 of 7 not expected. Many studies indicated that the mainten- time, the authors evaluated the efficacy and safety of egg ance of tolerance status obtained with the OIT required OIT in the same participants treated up to 4 years [51]. constant exposure to the food allergen [23, 45–47]. In Long-term follow-up questionnaires were administered 2012 the term “sustained unresponsiveness” (SU) was in- after study conclusion (LFQ-1) and 1 year later (LFQ-2) troduced for the first time [48], describing the ability of to assess possible effects of the lifestyle on the outcomes a food allergic subject, successfully desensitized with of the study. At Years 3 and 4, all subjects treated with OIT, to pass an oral food challenge (OFC) conducted egg OIT underwent a 10 g (cumulative dose) OFC to generally 28 weeks after stopping the food allergen ex- egg white powder to assess desensitization. Those who posure. Patients getting SU from their OIT will be passed the desensitization OFC discontinued OIT dosing allowed to introduce a previously allergenic food into for 4–6 weeks and had a second OFC (10 g as a cumula- their diet ad libitum, as happens to subjects who spon- tive dose), to assess for SU. At the fourth year of treat- taneously acquire a clinical tolerance. ment, the percentage of patients who achieved SU rose During the last 5 years, several clinical studies have to 50% (20/40). During both LFQ periods, the egg OIT– been proposed to demonstrate the achievement of a SU SU group showed a greater consumption of unbaked in food allergic patients. Currently available data concern and baked egg in terms of frequency and amount com- patients with cow’s milk, hen’s egg and peanut allergy. pared to egg OIT-desensitized group. At year 4, subjects Considering that children allergic to milk and egg are achieving SU had higher IgG4 values (p = 0.001) and most likely going to outgrow spontaneously their food lower egg skin prick test scores (p = 0.0002) over time allergies, all available data must be critically reviewed. In and a lower median baseline ratio of egg-specific IgE to this regard, the age of enrollment should not be under- total IgE (1.1% vs. 2.7%, p = 0.04). estimated. All clinical trials [36, 49–54] published on SU Recently, a 71% (15/21) SU to egg was reported 2 achieved after an OIT with cow’s milk and hen’s egg are weeks after the discontinuation of a low-dose (1/32 egg) expected to enroll food allergic subjects aged over 5 years OIT, carried out for 12 months [50]. (Table 1). Different dosing schedules and varying dura- The efficacy of a short-course egg OIT to induce SU was tions in terms of maintenance phase and food avoidance also reported. Thirty-seven per cent of patients (11/30) period also make comparison between trials difficult. passed an OFC performed at 4 months after a 30-day Based on the available data, the percentage of milk- and avoidance period [49]. These tolerance rates clearly exceed egg-allergic subjects achieved SU after an OIT ranges those expected from the natural history of egg allergy from 21% to 58,3% in a few years. resolution. If these data will be confirmed, OIT should be considered a disease-modifying treatment in egg allergy. Egg Burks and colleagues [48, 51] published their experience Milk with OIT in egg allergic individuals by analyzing the re- A milk OIT, supported by the simultaneous use of omali- sults obtained at 2 and 4 years from the beginning of the zumab, was also reported to be associated with SU [53]. research protocol. The goal was to desensitize the sub- At month-28, omalizumab was discontinued and subjects jects to 2 g of egg-white powder, achieved by just under passing an OFC continued OIT for 8 weeks, after which 50% (18/40) of subjects randomized to the active pro- OIT was discontinued with re-challenge at month-32. SU cedure group within the first 10 months. At 10 months was demonstrated in 13/27 (48.1%) of the active group. and 22 months, all participants underwent an OFC con- Afterwards, the authors sought to investigate mechanisms sisting of 5 g and 10 g (cumulative dose) of egg-white by which omalizumab modulates immunity in the context powder respectively. At 22 months, 30 of 40 children of OIT and to identify baseline biomarkers that predict (75%) in the OIT group successfully passed the chal- subgroups of patients most likely to benefit from lenge, discontinued OIT and avoided all egg consump- omalizumab [55]. A reduction of milk-induced basophil tion for 4 to 6 weeks. At 24 months, these children CD63 expression was observed in omalizumab- and underwent an OFC with 10 g of egg-white powder to placebo-treated subjects. However, IgE dependent hista- test for sustained unresponsiveness and 11 (27.5%) suc- mine release increased in washed cell preparations only cessfully passed the challenge (P = 0.03, as compared from omalizumab-treated subjects. Baseline basophil with placebo) with the resulting instruction to add egg CD63 expression was strongly associated with the to their diet ad libitum without specific recommendation occurrence of symptoms during OIT. The degree of on frequency, amount, or type of egg product. Consider- suppression in milk-induced CD63 expression at months ing the immune markers measured, small wheal diame- 28 and 32 was associated with the likelihood of passing an ters on skin-prick testing and increases in egg-specific OFC at these visits, suggesting that inhibition of basophil IgG4 antibody levels were associated with passing the reactivity might be central to the underlying mechanisms oral food challenge at 24 months. At a later point of responsible for desensitization to milk. The combination Pecora et al. World Allergy Organization Journal (2018) 11:11 Page 4 of 7 Table 1 Characteristics and results of hen’s egg and cow’s milk OIT RCTs Egg Burks et al. (2012) Escudero et al. (2015) Yanagida et al. (2016) Jones et al. (2016) Study design RCT double blinded RCT, not blinded RCT, not blinded RCT, follow-up Age range (years) 5–11 (median age: 7 ys) 5–17 (median age: 8 ys) ≥55–11 (median age: 7 ys) Number of patients 40 30 21 40 (active group) Number of patients 15 31 12 15 (control group) Withdrew from therapy52 5 5 (active group) Withdrew from therapy20 0 2 (control group) OIT duration 22 months 3 months 10 weeks 48 months Maximum tolerated dose 2 g one undercooked egg 62–194 mg 2 g every 2 days DBPCFC after OIT in At month 10 (5 g) 100% positive Not performed Not performed Not performed placebo group DBPCFC after OIT in At month 10 22 negative (55%) (P < 0.001) Not performed Not performed Not performed active group At month 22 (10 g) 30 negative (75%) (P < 0.001) Time of elimination 4–64 2 4–6 diet (weeks) DBPCFC after At month 24 (10 g) At month 4 (3,6 g) At week 12 (3 g) At month 36 food avoidance 11 negative 1 negative in CG 0 negative in CG 18 negative (cumulative maximum dose) 11 negative in AG 7 negative in AG At month 48 20 negative Sustained unresponsiveness (%) 28 (P = 0.03) 37 33,3 (P = 0.032) 45% at year 3 50% at year 4 Milk Yanagida et al. (2015) Wood et al. (2016) Takahashi et al. (2016) Study design RCT, not blinded RCT, double blinded RCT, not blinded Age range (years) ≥57–35 5–17 AG median AG median 9 years 11.7 years CG median 7 years CG median 9.5 years Number of patients 12 28 (OIT plus 31 (active group) omalizumab) Number of patients 25 29(OIT plus placebo) 17 (placebo group) Withdrew from therapy 0 2 0 at year 1 (active group) 11 at year 4 Withdrew from therapy05 0 (placebo group) OIT duration 12 months 30 months 4 years Maximum tolerated dose 3 ml 3.8 g 200 ml DBPCFC after OIT in 4 negative (3 ml) 20 negative (10 g) 0 negative (80 ml) placebo group DBPCFC after OIT in 9 negative (3 ml) 24 negative (10 g) 14 negative (80 ml) active group Pecora et al. World Allergy Organization Journal (2018) 11:11 Page 5 of 7 Table 1 Characteristics and results of hen’s egg and cow’s milk OIT RCTs (Continued) Time of elimination28 2 diet (weeks) DBPCFC after food avoidance At month 12.5 (3 ml) At month 12.5 (25 ml) At month 32 (10 g) At year 1 (80 ml) (cumulative maximum dose) 4 negative in CG 0 negative in CG 10 negative in CG 7 negative/31 7 negative in AG 4 negative in AG 13 negative in AG At year 2 (80 ml) 14 negative/30 Sustained unresponsiveness (%) 58.3% 33.3% 35.7% in CG At year 1 21% P = 0.018 P = 0.007 48.1% in AG At year 2 47% P = 0.008 of baseline basophil and serologic biomarkers allowed to immune response. The mechanisms inducing oral toler- define a subset of patients in which adjunctive therapy ance are manifold and involve allergen-specific Treg with omalizumab was associated with attainment of SU cells generated by mucosal DC, intestinal mucins and and a reduction in adverse reactions. Neither omalizumab- cytokines coming from epithelial cells and innate nor placebo-treated subjects exhibited a significant in- lymphoid cells. Gut-associated intestinal lymphoid tis- crease in the percentage of casein-specific Treg cells over sue discriminates between potentially harmful patho- the course of treatment. gens and non-harmful antigens, with a consequent The duration of maintenance phase appears to have a functional inactivation of lymphocyte following ad anti- decisive influence on the achievement of SU in cow’s gen encounter (such as food or commensal bacteria). In milk allergic subjects. To this end, a Japanese study addition, integrity of mucosal epithelial barrier and in- demonstrated that, 2 years after the start of OIT, the rate testinal homeostasis are influenced by the inflamma- of 2-weeks-SU in the active group significantly increased some pathway and production of IL-18 [34, 35]. As for compared with the rates at 1 year (P = 0.008) [54]. humoral mechanisms, the detection of allergen-specific There are many considerations to be made regarding IgG is especially associated with a clinical tolerance to the factors that might affect the achievement of a SU in foods. However, it is not clear if they represent an food allergic subjects after an OIT. First, the age bias active mechanism of immune tolerance or a mere con- could represent a decisive variable and future studies sequence of food exposure in subjects consuming aller- should investigate whether treatment outcomes regard- genic foods. ing desensitization or SU are influenced by OIT’s start- Important assessments to be consider before starting ing age. Second, the analysis of microbiome of food an OIT include the type of offending food/s and the age allergic subjects before and after OIT could provide of allergic subjects. Indeed, at least 80% of milk- and useful information regarding the achievement of egg-allergic children are expected to achieve spontan- desensitization or SU [56]. Third, clinical tolerance in- eous clinical tolerance by the school age, whereas the duced by food immunotherapy is associated with percentage falls to 10–20% in the case of peanut- or tree changes in basophils, IgG , allergen-specific Th2 cells, nut–allergic subjects [57, 58]. For this reason, the OIT’s and allergen-specific cells with regulatory markers. The starting age is crucial to achieve reliable results espe- identification of significant changes from the baseline, cially in the case of milk or egg allergic patients. correlated with SU, would be helpful to provide the ne- The spontaneous resolution of food allergy in children cessary dietary information to patients. Unlike SU, the is associated with an increased frequency of peripheral + + state of desensitization requires to continue a regular al- blood CD4 CD25 Tregs after an OFC and a reduced lergen intake indispensable to maintain the established proliferation of food allergen specific T cells [59, 60]. + + regs tolerance. Forth, the food habits in terms of frequency, The depletion of CD4 CD25 T restores the in vitro amount, or type of food product consumed (unbaked proliferative response in food allergen tolerant and baked) seem to directly influence the achievement individuals [53]. of SU. Fifth, long-term follow-up studies on OIT will The literature data certainly support the hypothesis allow to obtain a global view with the consequence of that the OIT is able to accelerate the resolution of food identifying possible factors likely to predispose food allergy. Indeed, this type of treatment aims to re- allergic subjects to achievement SU. introduce safely the offending food into the diet in a relatively short time. The OIT is associated with a Conclusion suppression of mast cell and basophil reactivity, with a Despite a growing knowledge about the pathophysio- consequent reduction of allergen-specific IgE and simul- logic mechanisms underlying allergic diseases, immune taneous increase of allergen-specific IgG4 antibodies. responses associated with tolerance still need investiga- Subjects successfully treated with OIT showed changes tion. Oral tolerance represents an active regulatory in allergen-specific cells with regulatory markers, in Pecora et al. World Allergy Organization Journal (2018) 11:11 Page 6 of 7 + + particular Foxp3 and LAP Tregs, which seem to play a 7. Reese I, Holzhauser T, Schnadt S, Dölle S, Kleine-Tebbe J, Raithel M, et al. Allergen and allergy risk assessment, allergen management, and gaps in the central role in inducing long-term tolerance. The lack of European food information regulation (FIR): are allergic consumers acquisition regarding the SU in all treated patients un- adequately protected by current statutory food safety and labeling derlies significant differences in individual immune re- regulations? Allergo J Int. 2015;24:180–4. 8. Dunn Galvin A, Chan CH, Crevel R, Grimshaw K, Poms R, Schnadt S, et al. sponse. In this context, emphasis should be placed on a Precautionary allergen labelling: perspectives from key stakeholder groups. more comprehensive understanding of mechanisms Allergy. 2015 Sep;70(9):1039–51. underlying the induction of oral tolerance with immuno- 9. Giovannini M, D'Auria E, Caffarelli C, Verduci E, Barberi S, Indinnimeo L, et al. 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Cell. Association of allergen-specific regulatory T cells with the onset of clinical 2011;145(5):745–57. tolerance to milk protein. J Allergy Clin Immunol. 2009;123:43–52. 40. Akdis M, Akdis CA. Mechanisms of allergen-specific immunotherapy: multiple suppressor factors at work in immune tolerance to allergens. J Allergy Clin Immunol. 2014;133:621–31. 41. Dioszeghy V, Mondoulet L, Puteaux E, Dhelft V, Ligouis M, Plaquet C, et al. Differences in phenotype, homing properties and suppressive activities of regulatory T cells induced by epicutaneous, oral or sublingual immunotherapy in mice sensitized to peanut. Cell Mol Immunol. 2016 Apr 11; https://doi.org/10.1038/cmi.2016.14. [Epub ahead of print]. 42. Rifkin DB. Latent transforming growth factor-beta (TGF-beta) binding proteins: orchestrators of TGF-beta availability. J Biol Chem. 2005;280:7409–12. 43. Gandhi R, Farez MF, Wang Y, Kozoriz D, Quintana FJ, Weiner HL. Cutting edge: human latency-associated peptide+ T cells: a novel regulatory T cell subset. J Immunol. 2010;184(9):4620–4. 44. Leonard SA, Martos G, Wang W, Nowak-Węgrzyn A, Berin MC. Oral immunotherapy induces local protective mechanisms in the gastrointestinal mucosa. J Allergy Clin Immunol. 2012;129(6):1579–1587.e1. 45. Rolinck-Werninghaus C, Staden U, Mehl A, Hamelmann E, Beyer K, Niggemann B. Specific oral tolerance induction with food in children: transient or persistent effect on food allergy? Allergy. 2005;60(10):1320–2. 46. Keet CA, Frischmeyer-Guerrerio PA, Thyagarajan A, Schroeder JT, Hamilton RG, Boden S, et al. The safety and efficacy of sublingual and oral immunotherapy for milk allergy. J Allergy Clin Immunol. 2012;129(2):448–55. 455.e1-5 47. Gorelik M, Narisety SD, Guerrerio AL, Chichester KL, Keet CA, Bieneman AP, et al. Suppression of the immunologic response to peanut during immunotherapy is often transient. J Allergy Clin Immunol. 2015;135(5):1283–92. 48. Burks AW, Jones SM, Wood RA, Fleischer DM, Sicherer SH, Lindblad RW, et al. Oral immunotherapy for treatment of egg allergy in children. N Engl J Med. 2012;367(3):233–43. 49. Escudero C, Rodríguez Del Río P, Sánchez-García S, Pérez-Rangel I, Pérez- Farinós N, García-Fernández C, et al. Early sustained unresponsiveness after short-course egg oral immunotherapy: a randomized controlled study in egg-allergic children. Clin Exp Allergy. 2015;45(12):1833–43. 50. Yanagida N, Sato S, Asaumi T, Nagakura K, Ogura K, Ebisawa M. Safety and Submit your next manuscript to BioMed Central efficacy of low-dose oral immunotherapy for Hen's egg allergy in children. Int Arch Allergy Immunol. 2016;171(3–4):265–8. and we will help you at every step: 51. Jones SM, Burks AW, Keet C, Vickery BP, Scurlock AM, Wood RA, et al. Long- • We accept pre-submission inquiries term treatment with egg oral immunotherapy enhances sustained unresponsiveness that persists after cessation of therapy. J Allergy Clin � Our selector tool helps you to find the most relevant journal Immunol. 2016;137(4):1117–1127.e10. � We provide round the clock customer support 52. Yanagida N, Sato S, Asaumi T, Okada Y, Ogura K, Ebisawa M. A single-center, � Convenient online submission case-control study of low-dose-induction oral immunotherapy with Cow's milk. Int Arch Allergy Immunol. 2015;168(2):131–7. � Thorough peer review 53. Wood RA, Kim JS, Lindblad R, Nadeau K, Henning AK, Dawson P, et al. A � Inclusion in PubMed and all major indexing services randomized, double-blind, placebo-controlled study of omalizumab � Maximum visibility for your research combined with oral immunotherapy for the treatment of cow's milk allergy. J Allergy Clin Immunol. 2016;137(4):1103–1110.e11. Submit your manuscript at www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png World Allergy Organization Journal Springer Journals

Debates in Allergy Medicine: Does oral immunotherapyshorten the duration of milk and egg allergy?The pro argument

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Abstract

The development of oral tolerance or food allergy is an active process, related to dynamic interactions between host immune cells, microbiome, dietary factors, and food allergens. Oral tolerance is the default immune response in the gut. A food allergy occurs when this process fails and a pathologic Th2 response is activated. Oral food immunotherapy (OIT) aims to restore immune tolerance in food-allergic individuals. The stimulation of Tregs production seems to represent a crucial step in inducing long-term tolerance, but other mechanisms (e.g., the suppression of mast cell and basophil reactivity, changes in allergen-specific cells with regulatory markers) are involved. Several studies reported the efficacy of OIT in terms of "sustained unresponsiveness" (SU), an operational definition of immune tolerance. In successfully treated subjects, the ability to pass an oral food challenge 2 to 8 weeks after stopping the food allergen exposure seems to be conditioned by the treatment starting age, frequency, amount or type of food consumed, and by the duration of the maintenance phase. Based on the available data, the percentage of milk- and egg-allergic subjects achieving sustained unresponsiveness after an OIT ranges from 21% to 58,3%. A comprehensive understanding of mechanisms underlying the induction of oral tolerance with OIT, or natural tolerance to food allergens in healthy individuals, could potentially lead to advances in development of better treatment options for food allergic patients. Keywords: Cow’s milk, Desensitization, Hen’s egg, Oral immunotherapy, Oral tolerance, Sustained unresponsiveness Background Therefore, considering the increasing prevalence of food Despite increasing knowledge in oral tolerance, the allergy [10, 11] with a significant impact on the public current standard of care in treating food allergy accord- health in industrialized countries [12], attempts to mod- ing to the international guidelines is still a strict elimin- ify the immune response to foods are a required choice, ation diet [1–6]. However, the dietary approach has particularly in severe food allergies [13]. Oral immuno- several limitations. First, the risk for severe systemic re- therapy (OIT) aims to do so through food exposure. actions due to the presence of hidden allergens [7, 8]in The first report of successful desensitization per- food products in spite of best efforts at strictly avoiding formed in a hen’s egg allergic patient dates back to 1908 food allergens. Second, avoidance diets may be associ- [14], and until the end of the 1990s only a few sporadic ated to the risk of nutritional deficiencies and impaired cases were reported [15, 16]. The use of subcutaneous growth especially if the food/s involved represent route was related to high-risk of severe systemic reac- fundamental component of the conventional diet (such tions [17, 18] and was quickly abandoned. Starting from as cow’s milk or hen’s egg) [9]. Third, inadvertent the end of the twentieth Century, an increasing number exposure to food ingredients is an everyday risk. of OIT studies was reported in the literature. In addition to case reports [19, 20], clinical trials on OIT as an ef- fective treatment for food allergy began to be published * Correspondence: valentina.pecora@opbg.net Division of Allergy, IRCCS Ospedale Pediatrico Bambino Gesù, Piazza Sant’Onofrio, 4, 00165 Rome, Italy © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Pecora et al. World Allergy Organization Journal (2018) 11:11 Page 2 of 7 [21–24]. A hundred years after the first report, inter- T cell due to a functionally inactivation of lymphocyte national scientific societies became interested in OIT. following an antigen encounter, such as food or com- With the resulting exponential increase in the number mensal bacteria [34]. of clinical trials published, metanalyses became possible The intestinal microbiota varies between individuals, [25–29]. Their current evidence suggests a proved effi- and plays key roles in defense against pathogens as well cacy in short-term tolerance, while information on long- as food digestion and nutrition. In case of dietary term outcomes is limited and mostly focused on milk changes, a modification in bacterial metabolites (such as OIT. The long-term follow-up studies [30–33] have pro- short-chain fatty acids that derive from fermentation of posed to evaluate only the regular intake of the incrimi- dietary fibers) is observed, with repercussions on muco- nated food, sometimes reporting adverse reactions sal integrity and inflammasome activation [37]. The occurred during the follow-up period. Side effects com- inflammasome pathway and production of the cytokine monly reported in the literature are the main weakness interleukin (IL)-18 are critical for intestinal homeostasis of this treatment, which is still not recommended in the and epithelial integrity by ensuring repair and cell sur- routine clinical practice. Generally, most reactions aris- vival under stress conditions [38, 39]. ing from clinical trials are mild and limited to the oro- pharynx resolving without intervention or with Immunomodulation during a specific food allergen antihistamine alone. However, systemic or severe reac- immunotherapy tions do not seem unlikely and are most frequent during The goal of food immunotherapy (oral, sublingual or epi- the build-up phase commonly conducted under phys- cutaneous) is to modify the immune response towards ician supervision. food protein antigens. Many studies report suppression of mast cell and basophil reactivity, a reduction of allergen- Oral tolerance to food protein in the gut specific IgE and a simultaneous increase of allergen- The gastrointestinal tract is the major route of exposure specific IgG4 antibodies [40, 41]. At the same time, the to food allergens and the largest reservoir of immune cells interest of researchers was focused on Tregs, and specific- in the body. Intestinal commensal bacteria induce protect- ally on two different populations: CD4 + CD25+ forkhead ive and regulatory responses that maintain host-microbial box P3 (Foxp3) Treg cells and Th3 cells. The inhibitory mutualism, and the mucosal immune system plays a cru- cytokine TGF-β is responsible for the mechanism of sup- cial role protecting the gastrointestinal tract from invading pression provided by Th3 cells expressing a late-stage pathogens and keeping the commensal microbiota com- Treg activation marker, latency associated peptide (LAP), partmentalized. The epithelial cells, responsible for separ- which forms a complex with TGF-β [42, 43]. Based on the ating the mucosal immune system from the gut lumen, recent evidences [41], Foxp3+ Tregs were induced by the secrete a number of factors that contribute to barrier func- three treatment routes but in particular by epicutaneous reg tion, including mucins, antimicrobial peptides, and trefoil immunotherapy (EPIT). LAP+ T levels increase in EPIT factors. This type of cells also transport antibodies, par- and OIT, whereas IL-10 cells are induced by sublingual ticularly IgA, into the intestinal lumen where these anti- immunotherapy (SLIT). The suppressive activity of EPIT- regs bodies can contribute to barrier function by excluding the induced T required cytotoxic T-lymphocyte antigen 4 uptake of antigens or microbes [34]. The resident immune (CTLA-4), whereas SLIT is strictly dependent on IL-10 cells, located inside the matrix of the Peyer’spatches, in- and OIT acted through both mechanisms. IL-10 repre- + + clude CD4 and CD8 T effector and regulatory T cells sents a key cytokine inhibiting INF-γ and IL-2 secretion regs (T ), B cells, macrophages and dendritic cells. The latter by Th1 cells and IL-4/IL-5 production by Th2 cells. The reg in particular are critical for maintaining immune stimulation of T production seems to represent a homeostasis within the gut. Their major functions crucial step in inducing long-term tolerance. A boosting concern the processing and the presentation of antigens, a of antigen-specific serum IgA level was observed in a critical step in the activation of T cells. In detail, CD103 mouse model of food OIT [44]. In this case the dendritic cells in the mesenteric lymph nodes express high neutralization by allergen-specific IgA would demonstrate levels of the enzyme retinal dehydrogenase 2 (RALDH2), a protective role. In addition, according to the murine which converts retinal to retinoic acid promoting gut- model the OIT protection would be localized to the homing activity and development of Tregs from naïve T gastrointestinal tract with significant downregulation of cells as well as secretion of transforming growth factor β gastrointestinal gene expression [44]. (TGF-β)[35, 36]. Gut-associated intestinal lymphoid tissue discriminates Could OIT be conceived of as a disease-modifying between potentially harmful pathogens and non-harmful treatment? antigens. Therefore, it is possible to observe an activa- Until a few years ago, the possibility that OIT could be tion of a protective immune response or an ‘off ’ state of able to modify the natural history of food allergy was Pecora et al. World Allergy Organization Journal (2018) 11:11 Page 3 of 7 not expected. Many studies indicated that the mainten- time, the authors evaluated the efficacy and safety of egg ance of tolerance status obtained with the OIT required OIT in the same participants treated up to 4 years [51]. constant exposure to the food allergen [23, 45–47]. In Long-term follow-up questionnaires were administered 2012 the term “sustained unresponsiveness” (SU) was in- after study conclusion (LFQ-1) and 1 year later (LFQ-2) troduced for the first time [48], describing the ability of to assess possible effects of the lifestyle on the outcomes a food allergic subject, successfully desensitized with of the study. At Years 3 and 4, all subjects treated with OIT, to pass an oral food challenge (OFC) conducted egg OIT underwent a 10 g (cumulative dose) OFC to generally 28 weeks after stopping the food allergen ex- egg white powder to assess desensitization. Those who posure. Patients getting SU from their OIT will be passed the desensitization OFC discontinued OIT dosing allowed to introduce a previously allergenic food into for 4–6 weeks and had a second OFC (10 g as a cumula- their diet ad libitum, as happens to subjects who spon- tive dose), to assess for SU. At the fourth year of treat- taneously acquire a clinical tolerance. ment, the percentage of patients who achieved SU rose During the last 5 years, several clinical studies have to 50% (20/40). During both LFQ periods, the egg OIT– been proposed to demonstrate the achievement of a SU SU group showed a greater consumption of unbaked in food allergic patients. Currently available data concern and baked egg in terms of frequency and amount com- patients with cow’s milk, hen’s egg and peanut allergy. pared to egg OIT-desensitized group. At year 4, subjects Considering that children allergic to milk and egg are achieving SU had higher IgG4 values (p = 0.001) and most likely going to outgrow spontaneously their food lower egg skin prick test scores (p = 0.0002) over time allergies, all available data must be critically reviewed. In and a lower median baseline ratio of egg-specific IgE to this regard, the age of enrollment should not be under- total IgE (1.1% vs. 2.7%, p = 0.04). estimated. All clinical trials [36, 49–54] published on SU Recently, a 71% (15/21) SU to egg was reported 2 achieved after an OIT with cow’s milk and hen’s egg are weeks after the discontinuation of a low-dose (1/32 egg) expected to enroll food allergic subjects aged over 5 years OIT, carried out for 12 months [50]. (Table 1). Different dosing schedules and varying dura- The efficacy of a short-course egg OIT to induce SU was tions in terms of maintenance phase and food avoidance also reported. Thirty-seven per cent of patients (11/30) period also make comparison between trials difficult. passed an OFC performed at 4 months after a 30-day Based on the available data, the percentage of milk- and avoidance period [49]. These tolerance rates clearly exceed egg-allergic subjects achieved SU after an OIT ranges those expected from the natural history of egg allergy from 21% to 58,3% in a few years. resolution. If these data will be confirmed, OIT should be considered a disease-modifying treatment in egg allergy. Egg Burks and colleagues [48, 51] published their experience Milk with OIT in egg allergic individuals by analyzing the re- A milk OIT, supported by the simultaneous use of omali- sults obtained at 2 and 4 years from the beginning of the zumab, was also reported to be associated with SU [53]. research protocol. The goal was to desensitize the sub- At month-28, omalizumab was discontinued and subjects jects to 2 g of egg-white powder, achieved by just under passing an OFC continued OIT for 8 weeks, after which 50% (18/40) of subjects randomized to the active pro- OIT was discontinued with re-challenge at month-32. SU cedure group within the first 10 months. At 10 months was demonstrated in 13/27 (48.1%) of the active group. and 22 months, all participants underwent an OFC con- Afterwards, the authors sought to investigate mechanisms sisting of 5 g and 10 g (cumulative dose) of egg-white by which omalizumab modulates immunity in the context powder respectively. At 22 months, 30 of 40 children of OIT and to identify baseline biomarkers that predict (75%) in the OIT group successfully passed the chal- subgroups of patients most likely to benefit from lenge, discontinued OIT and avoided all egg consump- omalizumab [55]. A reduction of milk-induced basophil tion for 4 to 6 weeks. At 24 months, these children CD63 expression was observed in omalizumab- and underwent an OFC with 10 g of egg-white powder to placebo-treated subjects. However, IgE dependent hista- test for sustained unresponsiveness and 11 (27.5%) suc- mine release increased in washed cell preparations only cessfully passed the challenge (P = 0.03, as compared from omalizumab-treated subjects. Baseline basophil with placebo) with the resulting instruction to add egg CD63 expression was strongly associated with the to their diet ad libitum without specific recommendation occurrence of symptoms during OIT. The degree of on frequency, amount, or type of egg product. Consider- suppression in milk-induced CD63 expression at months ing the immune markers measured, small wheal diame- 28 and 32 was associated with the likelihood of passing an ters on skin-prick testing and increases in egg-specific OFC at these visits, suggesting that inhibition of basophil IgG4 antibody levels were associated with passing the reactivity might be central to the underlying mechanisms oral food challenge at 24 months. At a later point of responsible for desensitization to milk. The combination Pecora et al. World Allergy Organization Journal (2018) 11:11 Page 4 of 7 Table 1 Characteristics and results of hen’s egg and cow’s milk OIT RCTs Egg Burks et al. (2012) Escudero et al. (2015) Yanagida et al. (2016) Jones et al. (2016) Study design RCT double blinded RCT, not blinded RCT, not blinded RCT, follow-up Age range (years) 5–11 (median age: 7 ys) 5–17 (median age: 8 ys) ≥55–11 (median age: 7 ys) Number of patients 40 30 21 40 (active group) Number of patients 15 31 12 15 (control group) Withdrew from therapy52 5 5 (active group) Withdrew from therapy20 0 2 (control group) OIT duration 22 months 3 months 10 weeks 48 months Maximum tolerated dose 2 g one undercooked egg 62–194 mg 2 g every 2 days DBPCFC after OIT in At month 10 (5 g) 100% positive Not performed Not performed Not performed placebo group DBPCFC after OIT in At month 10 22 negative (55%) (P < 0.001) Not performed Not performed Not performed active group At month 22 (10 g) 30 negative (75%) (P < 0.001) Time of elimination 4–64 2 4–6 diet (weeks) DBPCFC after At month 24 (10 g) At month 4 (3,6 g) At week 12 (3 g) At month 36 food avoidance 11 negative 1 negative in CG 0 negative in CG 18 negative (cumulative maximum dose) 11 negative in AG 7 negative in AG At month 48 20 negative Sustained unresponsiveness (%) 28 (P = 0.03) 37 33,3 (P = 0.032) 45% at year 3 50% at year 4 Milk Yanagida et al. (2015) Wood et al. (2016) Takahashi et al. (2016) Study design RCT, not blinded RCT, double blinded RCT, not blinded Age range (years) ≥57–35 5–17 AG median AG median 9 years 11.7 years CG median 7 years CG median 9.5 years Number of patients 12 28 (OIT plus 31 (active group) omalizumab) Number of patients 25 29(OIT plus placebo) 17 (placebo group) Withdrew from therapy 0 2 0 at year 1 (active group) 11 at year 4 Withdrew from therapy05 0 (placebo group) OIT duration 12 months 30 months 4 years Maximum tolerated dose 3 ml 3.8 g 200 ml DBPCFC after OIT in 4 negative (3 ml) 20 negative (10 g) 0 negative (80 ml) placebo group DBPCFC after OIT in 9 negative (3 ml) 24 negative (10 g) 14 negative (80 ml) active group Pecora et al. World Allergy Organization Journal (2018) 11:11 Page 5 of 7 Table 1 Characteristics and results of hen’s egg and cow’s milk OIT RCTs (Continued) Time of elimination28 2 diet (weeks) DBPCFC after food avoidance At month 12.5 (3 ml) At month 12.5 (25 ml) At month 32 (10 g) At year 1 (80 ml) (cumulative maximum dose) 4 negative in CG 0 negative in CG 10 negative in CG 7 negative/31 7 negative in AG 4 negative in AG 13 negative in AG At year 2 (80 ml) 14 negative/30 Sustained unresponsiveness (%) 58.3% 33.3% 35.7% in CG At year 1 21% P = 0.018 P = 0.007 48.1% in AG At year 2 47% P = 0.008 of baseline basophil and serologic biomarkers allowed to immune response. The mechanisms inducing oral toler- define a subset of patients in which adjunctive therapy ance are manifold and involve allergen-specific Treg with omalizumab was associated with attainment of SU cells generated by mucosal DC, intestinal mucins and and a reduction in adverse reactions. Neither omalizumab- cytokines coming from epithelial cells and innate nor placebo-treated subjects exhibited a significant in- lymphoid cells. Gut-associated intestinal lymphoid tis- crease in the percentage of casein-specific Treg cells over sue discriminates between potentially harmful patho- the course of treatment. gens and non-harmful antigens, with a consequent The duration of maintenance phase appears to have a functional inactivation of lymphocyte following ad anti- decisive influence on the achievement of SU in cow’s gen encounter (such as food or commensal bacteria). In milk allergic subjects. To this end, a Japanese study addition, integrity of mucosal epithelial barrier and in- demonstrated that, 2 years after the start of OIT, the rate testinal homeostasis are influenced by the inflamma- of 2-weeks-SU in the active group significantly increased some pathway and production of IL-18 [34, 35]. As for compared with the rates at 1 year (P = 0.008) [54]. humoral mechanisms, the detection of allergen-specific There are many considerations to be made regarding IgG is especially associated with a clinical tolerance to the factors that might affect the achievement of a SU in foods. However, it is not clear if they represent an food allergic subjects after an OIT. First, the age bias active mechanism of immune tolerance or a mere con- could represent a decisive variable and future studies sequence of food exposure in subjects consuming aller- should investigate whether treatment outcomes regard- genic foods. ing desensitization or SU are influenced by OIT’s start- Important assessments to be consider before starting ing age. Second, the analysis of microbiome of food an OIT include the type of offending food/s and the age allergic subjects before and after OIT could provide of allergic subjects. Indeed, at least 80% of milk- and useful information regarding the achievement of egg-allergic children are expected to achieve spontan- desensitization or SU [56]. Third, clinical tolerance in- eous clinical tolerance by the school age, whereas the duced by food immunotherapy is associated with percentage falls to 10–20% in the case of peanut- or tree changes in basophils, IgG , allergen-specific Th2 cells, nut–allergic subjects [57, 58]. For this reason, the OIT’s and allergen-specific cells with regulatory markers. The starting age is crucial to achieve reliable results espe- identification of significant changes from the baseline, cially in the case of milk or egg allergic patients. correlated with SU, would be helpful to provide the ne- The spontaneous resolution of food allergy in children cessary dietary information to patients. Unlike SU, the is associated with an increased frequency of peripheral + + state of desensitization requires to continue a regular al- blood CD4 CD25 Tregs after an OFC and a reduced lergen intake indispensable to maintain the established proliferation of food allergen specific T cells [59, 60]. + + regs tolerance. Forth, the food habits in terms of frequency, The depletion of CD4 CD25 T restores the in vitro amount, or type of food product consumed (unbaked proliferative response in food allergen tolerant and baked) seem to directly influence the achievement individuals [53]. of SU. Fifth, long-term follow-up studies on OIT will The literature data certainly support the hypothesis allow to obtain a global view with the consequence of that the OIT is able to accelerate the resolution of food identifying possible factors likely to predispose food allergy. Indeed, this type of treatment aims to re- allergic subjects to achievement SU. introduce safely the offending food into the diet in a relatively short time. The OIT is associated with a Conclusion suppression of mast cell and basophil reactivity, with a Despite a growing knowledge about the pathophysio- consequent reduction of allergen-specific IgE and simul- logic mechanisms underlying allergic diseases, immune taneous increase of allergen-specific IgG4 antibodies. responses associated with tolerance still need investiga- Subjects successfully treated with OIT showed changes tion. Oral tolerance represents an active regulatory in allergen-specific cells with regulatory markers, in Pecora et al. World Allergy Organization Journal (2018) 11:11 Page 6 of 7 + + particular Foxp3 and LAP Tregs, which seem to play a 7. Reese I, Holzhauser T, Schnadt S, Dölle S, Kleine-Tebbe J, Raithel M, et al. Allergen and allergy risk assessment, allergen management, and gaps in the central role in inducing long-term tolerance. The lack of European food information regulation (FIR): are allergic consumers acquisition regarding the SU in all treated patients un- adequately protected by current statutory food safety and labeling derlies significant differences in individual immune re- regulations? Allergo J Int. 2015;24:180–4. 8. Dunn Galvin A, Chan CH, Crevel R, Grimshaw K, Poms R, Schnadt S, et al. sponse. In this context, emphasis should be placed on a Precautionary allergen labelling: perspectives from key stakeholder groups. more comprehensive understanding of mechanisms Allergy. 2015 Sep;70(9):1039–51. underlying the induction of oral tolerance with immuno- 9. Giovannini M, D'Auria E, Caffarelli C, Verduci E, Barberi S, Indinnimeo L, et al. Nutritional management and follow up of infants and children therapy or natural tolerance to food allergens in healthy with food allergy: Italian Society of Pediatric Nutrition/Italian Society of individuals, to enable the development of better treat- Pediatric Allergy and Immunology Task Force Position Statement. Ital J ment options for food allergic patients. Pediatr. 2014;40:1. 10. Gupta RS, Springston EE, Warrier MR, Smith B, Kumar R, Pongracic J, et al. Abbreviations The prevalence, severity, and distribution of childhood food allergy in the CTLA-4: Cytotoxic T-lymphocyte antigen 4; EPIT: Epicutaneous United States. Pediatrics. 2011;128(1):e9–17. immunotherapy; Foxp3: Forkhead box P3; IL: Interleukin; LAP: Latency 11. Chafen JJ, Newberry SJ, Riedl MA, Bravata DM, Maglione M, Suttorp MJ, et associated peptide; OFC: Oral food challenge; OIT: Oral immunotherapy; al. Diagnosing and managing common food allergies: a systematic review. 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J Allergy Clin � Our selector tool helps you to find the most relevant journal Immunol. 2016;137(4):1117–1127.e10. � We provide round the clock customer support 52. Yanagida N, Sato S, Asaumi T, Okada Y, Ogura K, Ebisawa M. A single-center, � Convenient online submission case-control study of low-dose-induction oral immunotherapy with Cow's milk. Int Arch Allergy Immunol. 2015;168(2):131–7. � Thorough peer review 53. Wood RA, Kim JS, Lindblad R, Nadeau K, Henning AK, Dawson P, et al. A � Inclusion in PubMed and all major indexing services randomized, double-blind, placebo-controlled study of omalizumab � Maximum visibility for your research combined with oral immunotherapy for the treatment of cow's milk allergy. J Allergy Clin Immunol. 2016;137(4):1103–1110.e11. Submit your manuscript at www.biomedcentral.com/submit

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Published: Jun 15, 2018

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