The future of food allergy therapeutics

Food allergy is increasing in prevalence in westernized countries, leading to significant morbidity including nutritional deficiencies and growth delay as well as psychosocial burdens and the potential for fatal anaphylaxis. There is currently no effective form of therapy, and the mainstay of treatment remains strict avoidance. However, there are a number of promising therapeutic strategies currently being investigated for the treatment of food allergies. Allergen-specific approaches, such as various forms of immunotherapy, have been a major focus of investigation and appear to be promising methods of desensitization. More recently, the addition of anti-IgE monoclonal antibodies (mAbs) to immunotherapy regimens has been studied. Early work with antigen-fixed leukocytes in a murine model has shown promise in inducing tolerance, as have vaccines containing modified recombinant food proteins coadministered with heat-killed Escherichia coli. Nonspecific approaches include a Chinese herbal formulation, anti-IgE mAbs, and Trichuris suis ova therapy. The array of treatment modalities currently being investigated increases the likelihood of finding one or more effective therapies for the treatment of food allergy

Food allergen extracts to diagnose food-induced allergic diseases

OBJECTIVE: To review the manufacturing procedures of food allergen extracts and applicable regulatory requirements from government agencies, potential approaches to standardization, and clinical application of these products. The effects of thermal processing on allergenicity of common food allergens are also considered. DATA SOURCES: A broad literature review was conducted on the natural history of food allergy, the manufacture of allergen extracts, and the allergenicity of heated food. Regulations, guidance documents, and pharmacopoeias related to food allergen extracts from the United States and Europe were also reviewed. STUDY SELECTIONS: Authoritative and peer-reviewed research articles relevant to the topic were chosen for review. Selected regulations and guidance documents are current and relevant to food allergen extracts. RESULTS: Preparation of a food allergen extract may require careful selection and identification of source materials, grinding, defatting, extraction, clarification, sterilization, and product testing. Although extractions for all products licensed in the United States are performed using raw source materials, many foods are not consumed in their raw form. Heating foods may change their allergenicity, and doing so before extraction may change their allergenicity and the composition of the final product. CONCLUSION: The manufacture of food allergen extracts requires many considerations to achieve the maximal quality of the final product. Allergen extracts for a select number of foods may be inconsistent between manufacturers or unreliable in a clinical setting, indicating a potential area for future improvement

Is Clinical Tolerance Possible after Allergen Immunotherapy?

There is a growing evidence that allergen immunotherapy (AIT) can provide significant and long-lasting clinical benefit for a number of allergic individuals. However, it is less clear if AIT results in clinical tolerance, which is characterized by a persistent state of clinical non-reactivity to allergens after therapy is finished. Addressing this knowledge gap is particularly relevant for patients undergoing AIT for food allergies, as anything less than complete tolerance could have potentially devastating consequences. An increasing number of studies, in particular those involving oral immunotherapy, are attempting to assess tolerance induction following AIT. Clinical tolerance does appear to be achievable in a subset of patients undergoing AIT, but whether this is equivalent to the type of tolerance observed in nonallergic individuals remains unknown. Developing established criteria for assessing tolerance induction, as well as the use of consistent terminology when describing clinical tolerance, will be important for determining the disease-modifying potential of AIT

Mineral Intake and Status of Cowʼs Milk Allergic Infants Consuming an Amino Acid-based Formula:

Data on the mineral status of infants with cow's milk allergy (CMA) consuming an amino acid-based formula (AAF) have not been published. The present study aims to assess mineral status of term infants age 0 to 8 months diagnosed with CMA receiving an AAF for 16 weeks. Serum concentrations of calcium, phosphorus, chloride, sodium, potassium, magnesium, and ferritin were determined in 82 subjects at baseline and in 66 subjects after 16 weeks on AAF using standard methods and evaluated against age-specific reference ranges. In addition to this, individual estimated energy and mineral intakes were compared to Adequate Intakes defined by the European Food Safety Authority and the US Institute of Medicine. The results of this study show that the AAF was effective in providing an adequate mineral status in infants with CMA. The vast majority of infants aged 0 to 6 months (formula only) and aged 6 to 12 months (formula and complementary foods) had adequate mineral intakes

Clinical features of acute allergic reactions to peanut and tree nuts in children

Background. Peanut (PN) and tree nut (TN) allergies are potentially life-threatening, rarely outgrown, and appear to be increasing in prevalence. However, there is relatively little reported about the clinical features of acute reactions to these foods and their potential association. Objective. To describe the clinical features of acute reactions during initial and subsequent accidental ingestions of PN and TN among children with a history of at least one acute allergic reaction to these foods. Design. Questionnaire survey, examination, and serologic testing for specific IgE antibody of patients with convincing histories of acute reactions (at least one organ system involved within 60 minutes of ingestion) to PN or TN. Results. A total of 122 patients (63% males; median age, 8 years at time of study) had acute reactions; 68 had reactions only to PN, 20 only to TN, and 34 to both PN and TN. Of those reacting to TN, 34 had reactions to one, 12 to two, and 8 to three or more different TN, the most common being walnut, almond, and pecan. Initial reactions usually occurred at home (median age, 24 months for PN and 62 months for TN) and were considered to result from a first exposure in 72% of cases. Eighty-nine percent of the reactions involved the skin (urticaria, angioedema), 52% the respiratory tract (wheezing, throat tightness, repetitive coughing, dyspnea), and 32% the gastrointestinal tract (vomiting, diarrhea). Two organ systems were affected in 31% of initial reactions, and all three in 21% of reactions. Thirty-eight of 190 first reactions to PN or TN were treated with epinephrine. Accidental ingestions occurred in 55% of PN-allergic children (average of two accidents per patient with an accidental ingestion) and in 30% of TN-allergic children over a median period of 5.5 years. On average, symptoms after accidental exposure were generally similar to those at initial exposure. Accidents occurred commonly in school but also at home and in restaurants. Modes of accidental ingestion included sharing food, hidden ingredients, cross-contamination, and school craft projects using peanut butter. Eighty-three percent of the children were breastfed, with >90% of the mothers ingesting PN and at least one TN during lactation. Among patients reporting no history of exposure (>60% of patients for each TN), IgE antibodies were found to a particular TN in 50% to 82% of patients and to PN in 100% of patients. Conclusions. Acute allergic reactions to PN occur early in life. PN and TN allergic reactions coexist in one third of PN-allergic patients, frequently occur on first known exposure, and may be life-threatening, requiring emergency treatment. Accidental ingestions are common, occur frequently outside of the home, and often require emergency treatment. Consequently, early diagnosis followed by education on avoidance and treatment measures (including self-administered epinephrine) is imperative

Future therapies for food allergy

Food allergy affects 3.9% of US children and is increasing in prevalence. The current standard of care involves avoidance of the triggering food and treatment for accidental ingestions. While there is no current curative treatment, there are a number of therapeutic strategies under investigation. Allergen specific therapies include oral and sublingual immunotherapy with native food protein as well as recombinant food proteins. Allergen non-specific therapies include a Chinese herbal formula (FAHF-2) and the use of anti-IgE monoclonal antibody therapy. Although none of these treatments are ready for clinical use, these therapeutic strategies present promising options for the future of food allergy

Oral and sublingual immunotherapy for food allergy: current progress and future directions

Food allergies are increasing in prevalence and present an emerging epidemic for westernized countries. Strict dietary avoidance is the only approved management for food allergy, but accidental exposures regularly occur, leading to significant patient anxiety and decreased quality of life. Over the past decade, oral and sublingual immunotherapies have emerged as potential treatments for food allergy. While several small clinical trials have demonstrated that immunotherapy can desensitize food-allergic individuals, strategies for further enhancing safety and definitively establishing long-term efficacy are needed. This review presents an overview of recent oral and sublingual immunotherapy trials, and provides a glimpse into what the next generation of food immunotherapy may entail

The impact of plant biotechnology on food allergy

Concerns about food allergy and its societal growth are intertwined with the growing advances in plant biotechnology. The knowledge of plant genes and protein structures provides the key foundation to understanding biochemical processes that produce food allergy. Biotechnology offers the prospect of producing low-allergen or allergen null plants that could mitigate the allergic response. Modified low-IgE binding variants of allergens could be used as a vaccine to build immunotolerance in sensitive individuals. The potential to introduce new allergens into the food supply by biotechnology products is a regulatory concern. Introduction Food allergies are a growing concern in the industrialized countries where the percentage of the population that exhibit clinical food allergies has increased rapidly over the past few decades Plant biotechnology has had a major role in defining the problems of food allergy. Modifying food plants presents the potential to provide a means to address the problems of sensitization and management of food allergies. As plant biotechnology is used as production platforms to produce altered food and feed as well as industrial products there is potential that this will inadvertently produce potent food allergies is a risk, but how to define that risk is a continuing problem. Using the plant biotechnology tool kit and its implications for food defining allergy Biotechnology has revolutionized our understanding of which proteins are food allergens, how these proteins are related and often closely related to other members of the same family that are not known to be allergens. Using the sequence databases many food allergen proteins have had maps of antigenic sites produced and these antigenic sites have been placed on crystal structures. [5,6,7 ]. The interpretation from this is that only a small fraction of proteins, perhaps 2%, are allergens however this should be viewed with caution as the vast majority of proteins produced by any cell are accumulated at levels that are below the threshold for sensitization or hypersensitive Seed storage proteins including 2S albumins, 7 S vicilins, and 11 S legumin family of proteins include the most potent of the plant allergens responsible for most plantsource induced anaphylaxis deaths. The 2S storage proteins of tree nuts as well as the 2S proteins of sunflower and peanut result in instances of anaphylaxis death. Other seeds have abundant 2S proteins including the Brassicas and the Cucurbit squashes are much more rarely allergenic. Similar broad allergenic responses have demonstrated with the lipid transfer proteins (LTP) with many examples from seed and from vegetative parts of the plant such as tap-roots and fruit being dominant allergens [11 ]. LTP examples include carrot, peach, apple, beet-root as well as seeds including tree nuts and peanuts with some sensitive people broadly reactive to the LTPs of diverse species. Even in closely related plants such legume seeds where the 7S proteins of peanut and soybean are significant allergens while the homologous 7S proteins of the common green bean appears to be rarely allergenic. Altering plants and their allergens to mitigate food allegenicity Attempts have been made to reduce allergenicity by producing allergen-reduced or allergen-null plants by biotechnology or by selection as a proof of concept. These experiments have demonstrated that it is feasible to completely eliminate specific allergens from food plants. Beginning with the first attempts to partially silence the rice allergen [12,13], to completely eliminating a major allergen of soybean [14,15] [25 ,26 ,27 ]. This approach has been used for peanut and has resulted in identifying peanuts lines null for Ara h 2 the major demonstrated allergen [28,29 ]. One of the difficulties in using genetic modification or nulls to create low-allergen or hypoallergenic seeds is that for many seeds the allergenic proteins account for the dominant portion of the seed proteome A further complication in silencing part of a seed's protein content is that seeds generally appear to compensate for a shortfall of a major protein by accumulating other seed proteins to maintain a relatively constant protein content. Soybeans with silenced b-conglycinin storage protein the protein content was compensated by increased accumulation of glycinin storage protein that maintains the normal 39% protein level [14]. b-conglycinin is an established IgE binding protein so silencing removes one allergen replaced by glycinin also an IgE binding protein. Whether this is a net loss or gain of allergenicity has not been tested on sensitized people. This observation was one of the first of what is emerging to be a broader potential problem and opportunity with strategies to alter seed allergenicity by producing nulls of major seed allergens. Because each event of silencing a major protein, The IgE binding proteins of many allergenic seeds comprise the large majority of the seed's protein content. Soybean has 16 described allergens of which 7 (italics) are illustrated on the two dimensional gel of the total seed proteins. The pie chart shows the relative abundance of the 7 allergens determined by spot volume analysis that together are in excess of 60% of the total proteins. This illustrates the problem of modifying seeds to create allergen nulls with most of the protein content and valued nutritional composition being the seed allergens. Current Opinion in Biotechnology 2011, 22:224-230 www.sciencedirect.com Immunotherapy is a promising treatment approach for pre-existing food allergy where small and increasing doses of an antigen is given to a sensitive individual to build up immunotolerance ([37 ], for review). While many clinical tests of immunotherapy have been conducted with extracts of the whole allergenic source, peanut, for example, there is a biotechnological variant of this approach that may prove effective and suitable to standardize as a vaccine. With comprehensive transcript and genomic sequences the entire gene families encoding allergenic proteins have been determined. These sequences are used to produce comprehensive peptide maps of the allergen then the IgE binding sites for the gene family members can be determined (e.g. [8][9][10] Good gut health may have an important role in impeding the acquisition of food allergy. Gut health and general health can be improved by micronutrients and there many projects underway to produce functional foods with enhanced nutrient content ([37 ] for review). Among these micronutrients b-carotene produced in plants will on demand be cleaved to produce vitamin A. There are many projects underway to improve b-carotene content in plant foods of which the 'golden rice' project Food allergy and the deployment of plant biotechnology Two biotechnology-generated events catapulted the awareness of the potential for biotechnology to increased allergenic risk as a consequence of introducing new traits into plants. Most seeds do not possess an optimum balance of amino acids, fatty acids, and other constituents for use as food and feed. Among the earliest goals of plant biotechnology were efforts to rebalance essential amino acid content to be more aligned with food and feed needs. Among the strategies tested was the expression of highsulfur content 2S storage protein genes derived from the Brazil nut in soybean. The use of this strategy was aborted when it was recognized that the 2S storage proteins from tree nuts are potent allergens and correlated with potentially lethal anaphylaxis Biotechnology offers the prospect to express and accumulate essentially any protein from any source in plants. Laboratory-level studies have produced antibodies, vaccines, enzymes, food/feed proteins, and many other potential products in diverse plants. Plant-based production offers the economic advantages of mass protein production using the efficient multiplier of agricultural production. The continuing use, and need, for conventional crop plants as production platforms will require protocols to evaluate the potential for novel proteins including synthetic proteins to be food allergens. The impact of plant biotechnology on food allergy Herman and Burks 227 Conclusion

Prevalence of peanut and tree nut allergy in the US determined by a random digit dial telephone survey

Background: Allergy to peanuts and tree nuts (TNs) is one of the leading causes of fatal and near-fatal food-induced allergic reactions. These allergies can be lifelong and appear to be increasing in prevalence. Despite the seriousness of these allergies, the prevalence of peanut and TN allergy in the general population is unknown. Objective: We sought to determine the prevalence of peanut and TN allergy among the general population of the United States. Methods: We used a nationwide, cross-sectional, random digit dial telephone survey with a standardized questionnaire. Results: A total of 4374 households contacted by telephone participated (participation rate, 67%), representing 12,032 individuals. Peanut or TN allergy was self-reported in 164 individuals (1.4%; 95% confidence interval [CI], 1.2%-1.6%) in 151 households (3.5%; 95% CI, 2.9%-4.0%). The prevalence of reported allergy in adults (1.6%) was higher than that found in children under 18 years of age (0.6%). In 131 individuals, details of the reactions were obtained. When applying criteria requiring reactions to be typical of IgE-mediated reactions (hives, angioedema, wheezing, throat tightness, vomiting, and diarrhea) within an hour of ingestion, 10% of these subjects were excluded. Among the remaining 118 subjects, allergic reactions involved 1 organ system (skin, respiratory, or gastrointestinal systems) in 50 subjects, 2 in 45 subjects, and all 3 in 23 subjects. Forty-five percent of these 118 respondents reported more than 5 lifetime reactions. Only 53% of these 118 subjects ever saw a physician for the allergic reaction, and only 7% had self-injectable epinephrine available at the time of the interview. The prevalence of peanut and TN allergy was adjusted by assuming that 10% of the remaining 33 subjects without a description of their reactions would also be excluded and correcting for a 7% false-positive rate for the survey instrument. A final “corrected” prevalence estimate of 1.1% (95% CI, 1.0%-1.4%) was obtained. Conclusions: Peanut and/or TN allergy affects approximately 1.1% of the general population, or about 3 million Americans, representing a significant health concern. Despite the severity of reactions, about half of the subjects never sought an evaluation by a physician, and only a few had epinephrine available for emergency use

Diagnosis, Management, and Investigational Therapies for Food Allergies

Food allergies have increased in prevalence over the past 20 years, now becoming an important public health concern. Although there are no therapies currently available for routine clinical care, recent reports have indicated that immunotherapies targeting the mucosal immune system may be effective. Oral immunotherapy is conducted by administering small, increasing amounts of food allergen; it has shown promise for desensitizing individuals with peanut, egg, or milk allergies. Sublingual immunotherapy also desensitizes allergic patients to foods—2 major studies have examined the effects of sublingual immunotherapy in subjects with peanut allergies. We review the complex nature of IgE-mediated food allergies and the therapies being evaluated in clinical trials. We focus on the diagnosis and management of food allergies and investigational therapies