Mechanism and Control of Food Allergy

Lebensm.-Wiss. u.-Technol., 32, 1]11 Ž1999 .

Mechanism and Control of Food Allergy Kyoko Hayakawa, Yu-Yen Linko and Pekka Linko*

K. Hayakawa: Fukuoka Women Junior College, Gojo, Dazaifu-shi, 818-0117 ŽJapan. Y-Y. Linko, Pekka Linko: Laboratory of Bioprocess Engineering, Helsinki University of Technology, P.O. Box 6100, 02015 HUT ŽFinland. (Recei¨ ed June 2, 1998; accepted July 25, 1998)

The number of patients suffering from food allergy has increased strikingly during the last few decades, coinciding with changes in eating habits and in the en¨ ironment. Most food-born allergies are IgE-mediated immunologic reactions to specific foods. It is often difficult to diagnose true food allergy, because similar symptoms may be caused by naturally occurring toxins or chemical additi¨ es. This paper discusses the problems related to food allergy in general, the current knowledge of food allergies and the mechanisms in¨ ol¨ ed, anti-allergenic factors in foods, methods with which food allergy may be decreased and treated, relationships between lipid metabolism and allergy, effects of food processing and genetic engineering on food allergy, and recent progress in the de¨ elopment of hypoallergenic foods.

q 1999 Academic Press Keywords: fatty acid; food allergy; genetic engineering; hypersensitivity; hypoallergenic food; leukotriene

Introduction

above the upper limit of 25% of the energy supply recommended by the Japanese dietary allowances. At the same time, increased allergy against rice has become a problem, with rice ranking second after egg white as the most common potential allergen in Japan, Ž11.; this has prompted research into developing hypoallergenic rice. Most patients sensitive to rice are also sensitive to barley, corn and wheat, but not to millet. According to a French study, the sensitization to different foods has changed recently, with hypersensitivities to wheat, soy, peanuts, celery, mustard and rice definitely on the increase Ž12.. According to a 1995 consultation on food allergies by FAO, cow’s milk, crustacean, eggs, fish, peanuts, soybean, tree nuts and wheat are the most common allergenic foods accounting for over 90% of all serious allergic reactions to foods world wide Ž13.. Out of 40 reported severe reactions to foods recently reported in Sweden, peanuts and hazelnuts were the foods most frequently associated with life threatening reactions Ž14.. A number of fresh fruits and vegetables are also widely allergenic, although the symptoms caused are usually relatively mild and the allergens are often sensitive to cooking. Table 1 lists the important allergenic foods. The ‘Nutrition Classics’ paper of 1912 by Schloss Ž15. is one of the first that reports on immunological food sensitivity. It describes in detail the history of the development of marked allergic symtoms of a male infant to almonds, eggs and oatmeal. Prausnitz and Kustner Ž16. were the first to demonstrate in 1921 that

Although only about 2% of adults and 5% of children have been estimated to be sensitive to food-born allergens Ž1, 2., the number of patients suffering from food allergy has increased strikingly during recent decades, and allergic diseases have become a major clinical and public health problem Ž3, 4.. In this context, a European Food Intolerance Databanks project to provide information on safe foods for individuals with food allergies and intolerances should be mentioned Ž3, 5.. According to a U.S. Department of Agriculture report, as much as 15% of the U.S. population may be allergic to some food ingredients Ž2.. Similar observations have been reported elsewhere. At the same time concerns on occupational related hypersensitivity to foods Ž6, 7. and on increased reactions to food additives have been raised Ž8.. One of the reasons for the increase in food allergies is believed to be the changes that have taken place in eating habits and in the environment. With an increase in the popularity of seafood, reports on adverse reactions to these foods have mounted Ž9.. It has been estimated that the intake of potentially allergenic proteins has increased in Japan by about 17% with a decrease in the consumption of rice and an increase in the intake of meat, dairy products and fat Ž10.. Fat levels in the average Japanese diet have increased * To whom correspondence should be addressed.

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food antigens Ži.e. allergens . are rapidly absorbed from the gastrointestinal tract and transported to the various organs of the body. In 1959, Burnet proposed a theory describing the recognition of foreign antigens by lymphocytes and the subsequent induction of an immune response Ž17.. Food allergy is today recognized as an immunemediated state of hypersensitivity that results from an exposure to an allergen, usually a protein of food origin, sometimes also defined as type I allergy, an immunoglobulin E ŽIgE.-mediated immunologic reaction to specific foodŽs. Ž18, 19.. IgE is a special immunoglobulin that in some patients is directed against otherwise harmless glycoproteins which act as antigens Žoften referred to as allergens .. The clinical, immunological and nutritional factors related to food allergy have been discussed in a number of reviews Ž1, 2, 5, 20]24. and in the report of the related EU AAIR project on food allergies and intolerances Ž25.. It is often difficult to diagnose true food allergy, because similar symptoms may be caused by a number of other factors such as food intolerance, seafood toxins or chemical additives Ž13, 26, 27.. Consequently, the American Academy of Allergy and Immunology ŽAAAI. has defined adverse food allergy or hypersensitivity as ‘An immunologic reaction resulting from ingestion of a food or food additive. This reaction occurs only in some patients, may occur after only a small amount of the substance ingested, and is unrelated to any physiological effect of the food or the food additive’ Ž28.. The immunomechanism does not normally react against ‘essential food’ Ž29.. Most potentially antigenic material is broken down during the digestive process to be selectively absorbed in a nonantigenic form Ž3.. However, intact antigens Žallergens. do also penetrate the gastrointestinal barrier entering the body where they can cause hypersensitivity Žallergic reactions. Ž30.. As Lucretius said centuries ago: ‘One man’s food may be another man’s poison’ Ž31.. This report gives a concise state-of-the-art review on food allergy and its control.

any undesired problems related to the diet. It should only be used on nontoxic immune-mediated reactions, whereas food intolerance describes nontoxic, nonimmune-related mainly enzymatic or pharmacological dysfunctions such as lactose intolerance, anaphylactic reactions, scromboid fish Žhistamine. poisoning and, often inherited, metabolic reactions Ž32, 33.. Examples of nonIgE mediated diseases are celiac disease and protein-induced gastroenteropathy. A glossary of terms related to allergy is given in Table 2. Allergens are classified roughly into diet Žfood. allergens and inhaled allergens. Inhaled allergens may also be food-borne. Food allergens are taken in the diet and enter the interior of the body through the alimentary tract. Food allergens absorbed during digestion within the alimentary tract are distributed to the body via the blood stream, whereas inhalant allergens invade the body through air ducts or skin contact. The major identified food allergens and their characteristics have been described in detail by Bush and Hefle et al. Ž20. and Taylor and Lehrer Ž34.. Clinically, most patients react to only one or a few items from one food group, although they may also possess IgE antibody reactivity to other related food items. Food allergens can cause various symptoms such as anaphylaxis, oral tingling and swelling, atopic dermatitis Žskin rash. and urticaria Žhives., and gastrointestinal Žabdominal cramps, diarrhea, vomiting. and respiratory Žasthma, laryngeal edema, rhinitis . reactions Ž1.. In true food allergy gastrointestinal symptoms are most common Ž35.. Although respiratory symptoms such as asthma and rhinitis due to pollens are infrequent in food allergy, the initial contact in occupationally acquired food allergy in adults may be through inhalation, as in baker’s asthma, usually caused by wheat or rye flour Ž36.. Most bakers sensitized to flour can ingest bread without problems although bakery workers exposed to egg become reactive when egg is later ingested. Once induced, the allergic sensitivity is likely to persist for varying periods, possibly even for lifetime. Anaphylaxis is rare and can be rapidly fatal. Nearly all food allergens are proteins, although only a small proportion of proteins are allergens. More than 200 proteinaceous allergens have been identified and characterized, some from non food sources Ž37., and

Symptoms of Food Allergy The term food allergy is frequently misused to describe

Table 1 Common allergenic foods Cereal grain Milk Crustacean Eggs Fish Fruits and berries Spices Legumes Molluscs Tree nuts Vetetables

Barley, buckwheat, rice, rye, wheat Cow’s milk, etc. Crab, crayfish, lobster, shrimp, etc. Egg white and egg yolk of all avian eggs Cod, haddock, salmon, trout, etc. Apple, banana, guava, kiwi, papaya, peach, strawberry Cinnamon, mustard, etc. Castor bean, green pea, peanut, soybean Clam, oyster, scallop, squid, etc. Almond, Brazil nut, hazel nut, pistachio, walnut, etc. Celery, potato, tomato

Adapted from Taylor and Cumming Ž32..

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over 100 different foods or food components have been reported to have caused adverse reactions Ž38.. Most food allergens are with an acidic isoelectric point Ž34.. However, any food that contains protein may be potentially allergenic. The most allergenic proteins in milk are believed to be a s1 -casein and b-lactoglobulin; in egg white, ovomucoid; in soybean, the trypsin inhibitor; in peanuts, a large glycoprotein; Ž21.. The molecular mass range of food-born allergenic proteins varies from about 10 000]70 000. One of the largest is the peanut allergen, with a subunit molecular mass of 65 000 Ž39.. In comparison, the molecular mass of insulin is 6000, and of glucagon only 3800. Clearly, the isolation and identification of the causative allergenic molecules in foods is of utmost importance Ž39..

the basis of the immunologic mechanism. Type I allergy, so called immediate hypersensitivity reaction or anaphylaxis takes place when antigens such as certain proteins from food or pollen bind to specific IgE antibodies attached to the tissue mast cells or blood basophils, and eosinophils, and trigger from their granules the release of mediators such as histamine that cause the typical symptoms of allergy. Examples of symptoms include asthma, atopic dermatitis, rhinitis and urticaria. The type II or antibody-dependent cytotoxic hypersensitivity is both IgG and IgM mediated. The antibody binds to cell-bound antigen, leading to phagocytosis, cell destruction or cytolysis as in immune haemolytic anaemia. The type III hypersensitivity or Arthus reactions are mainly IgG mediated. The antibody-antigen complexes are formed in large quantities, leading to tissue injuries such as rheumatoid arthritis, serum sickness and vasculitis. Type IV hypersensitivity or delayed hypersensitivity is not mediated by antibodies but leads to the activation of T cells and to lymphokine production, mediating a number of inflammatory responses after a long delay. Typical examples are contact dermatitis and the tuberculin skin test. Types I to III are antibody mediated while type IV is mediated primarily by T-cell lymphocytes and macrophages Ž5.. Food related allergic diseases are mostly of Type I, resulting from IgE-mediated immune responses, type IV food allergies are also known but type II and III food allergies are rare Ž31.. Type IV

Classification of Hypersensitivity It has been shown that food intake is closely related to the immune system Ž40.. The function of the immune system is to recognize and eliminate harmful foreign agents, which are removed quickly and efficiently when the system functions properly. However, occasionally the immune system responds adversely to foreign proteins or allergens, causing allergic reactions. Thus, allergy can be considered as an example of the difficulties in maintaining homeostasis. According to Coombs and Gell Ž41. allergic responses or hypersensitivity may be classified into four types, on

Table 2 Glossary Allergen

A biological or chemical substance that induces an allergic reaction.

Allergenic

Ability of a substance to bind to IgE and elicit allergic symptoms.

Anaphylaxis

A generalized inflammatory immune response to an allergen in a sensitized individual that may be fatal. Food-related, exercise-induced anaphylactic uticaria and shock can also develop after performing vigorous exercise within 2 h of eating.

Antibody

A serum globulin protein molecule produced and secreted by B lymphocytes in response to a specific antigen, to which it is capable of binding.

Antigen

A foreign substance, usually a glycoprotein recognized by the immune system to stimulate an immune response.

Atopy

The genetic predisposition to allergy typical of subjects that produce greater quantities of specific immunoglobulin IgE in comparison to healthy individuals.

Epitope

A site on an antigen that interacts with the cells of the immune system by binding the antibody Že.g. B- or T-cell epitope..

Food Allergy

The immune-mediated state of hypersensitivity resulting from exposure to a food-borne allergen and not related to any physiological effect of the food or its component. The term is frequently misused to describe any undesired problem related to diet.

Histamine

An amine released in large amounts by mast cells, thereby triggering the symptoms of allergy.

Hypoallergenic food

Food modified by chemical, enzymatic or genetic means to possess less than normal allergenicity.

IgE

A specific class of immunoglobulin secreted by B cells, binding to specific receptors on mast cells. The most common allergic reaction is mediated by IgE.

IgG

One of the five classes of antibody molecules, the immunoglobulins IgA, IgD, IgE, IgG and IgM.

Leukotrienes

Mast cell released eicosanoid mediators derived from arachidonic acid.

Mast cells

Tissue cells of the immune system that release e.g. histamine in allergy.

Type I allergy

An IgE-mediated allergic reaction.

Adapted from Matsuda and Nakamura Ž21., and Taylor and Cumming Ž32.

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food allergy can also be accompanied by IgE mediated Type I hypersensitivity.

allergen, and a sufficient number of IgE molecules of high affinity for the same allergen should be present in the cell. Conversely, killer T-cells destroy antigen-infected cells by first binding to them and subsequently releasing a protein that perforates the plasma membrane of the infected cell, for example, by viruses.

Mechanism of Type I Food Allergy Type I allergy is an IgE antibody mediated immunologic reaction Ž2, 42, 43.. When various foods are ingested, IgE antibodies are produced in lymphocytes called B-cells, formed primarily in the bone marrow. B-cells have a high density of immunoglobulins on their surface, secreting IgE molecules which, after circulating for about 1 d in the blood eventually reach mast cells in the intestinal mucosa and trachea, or basophils in the blood. Mast cells are relatively large alpha cells, often with several IgE antibody receptors or binding sites called epitopes on their surface. Thus, the immune system will have several possible avenues of attack for naturally occurring antigens so the individual is now allergically sensitized. The specific membranebound IgE on the mast cells, basophils or eosinophils is able to recognize the same food antigen Žallergen., activating the cell and causing a chain of events that results in the release of histamine and other substances responsible for the allergic symptoms Ž5.. It is believed that these specialized cells act both as immunoregulators and effectors Ž44.. Another type of lymphocyte ŽT-cells., formed mostly in the thymus gland, lacks immunoglobulin, but has unique cell membrane receptors involved with antigen recognition and subsequent differentiation. The main function of B-cells is the production of antibody molecules in response to antigenic stimulation. Antibodies are serum proteins which react specifically to the antigen initially responsible for its production. There are five major classes of antibody molecules: IgM, IgG, IgA, IgD and IgE. The epitopes that react either with an antibody or antibody-producing B-cells are called B-cell epitopes and those reacting with T cells are called T-cell epitopes Ž37.. The so called helper T-cells ŽTh-1 and Th-2. control several of the B-cell functions. Th-1 lymphocytes release cytokines Žlymphokines., especially interleukins ŽIL-2,. and interferon-g ŽIFN-g . aiding in the proliferation of the B-cells and activating the Th-2 cells. IFN-g inhibits IgE production. The activated Th-2 lymphocytes primarily release the lymphokines interleukin-4 and -5 ŽIL-4 and IL-5. that affect the production of allergen-specific antibodies, as described above. Lymphokines affect B-cell differentiation with IL-4 responsible for the IgE production and IL-5 for IgA production. Once the allergen encounters the IgE sensitized mast cell during food ingestion, it cross-links the mast cell surface-bound IgE molecules to initiate degranulation and triggers the release of mediators such as histamine and leukotrienes that in turn elicit, within minutes, the clinical symptoms of allergic diseases such as asthma, eczema, hayfever, hives, and anaphylaxis Ž42.. The cross-linking theory implies that at least two IgE binding sites have to be available per

Polyunsaturated Fatty Acids and Allergy As has already been described above, there appears to be a clear connection between lipid metabolism and allergy, and the influence of fats in the onset of allergy seems possible. According to recent results, fat absorption has an important role in allergic response. The essential polyunsaturated fatty acids ŽPUFA. play an important regulating function in the allergic response, and to understand the relationships between allergy and nutritive fatty acids, the arachidonic acid cascade needs to be understood Ž45, 46.. The metabolic transformation of the arachidonic acid into physiologically active compounds such as prostaglandins ŽPGs., thromboxanes ŽTXs. and leukotrienes ŽLTs. is of major importance in hypersensitivity. The precursor of arachidonic acid is the dietary linoleic acid Žoctadecadienoic acid. Ž46, 47.. Arachidonic acid is a 20-carbon essential n-6 PUFA ŽC20:4v6. that was identified in the 1930s around the time that ‘prostaglandin’ activity was also first reported, but it took a quarter of a century before the first two prostaglandis were crystallized and their structure elucidated. Prostaglandins of the ‘3-series’ are derived from eicosapentaenoic acid ŽC20:5v3., which is abundant in fish. The formation of prostaglandins and thromboxanes is catalyzed by 1-cycloxygenase, while leukotrienes are formed from arachidonic acid by the peroxidative pathway, initially catalyzed by 5-lipoxygenase Ž48.. The physiologically active metabolites of arachidonic acid liberated from membrane phospholipids are generally called eicosanoids. The leukotrienes LTC 4 , LTD4 and LTE 4 are potent sustained smooth muscle constrictors that cause atopic dermatitis, diarrhea, and constriction of air passages in bronchi during an asthma attack. They are believed to have a key function in anaphylaxis, with the leukotriene LTE 4 having a high level of allergic response Ž46, 49.. Leukotrienes are synthesized from the arachidonic acid, lipoxygenase, in the membrane phospholipid and subsequently released from mast cells during IgE-type hypersensitivity reactions as the major mediators Ž50.. When the ratio of arachidonic acid to the total PUFAs is high, alpha cells are activated, and the arachidonic acid production rate increases. Accordingly, the formation of eicosanoids also increases. The ratio of AA to PUFA increases with an excessive ingestion of linolic acid. This increase is restrained with an uptake of n-3 PUFA, which suggests that the illness may be caused by a relative deficiency of n-3 PUFA. Similar results have been obtained by Hwang et al. Ž51. and Nakamura et al.. Ž52. with rats. Foods with a lower

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ratio of linoleic acid to n-3 PUFA resulted in a reduced formation of the AA and LTB 4 . The possible anti-allergenic activity of perilla leaf extract has been reported in Japan Ž53, 54.. Food allergenicity decreases with the inactivation or elimination of allergy accelerators, which can be achieved by the activation of or an increase in an allergen repressor. The anti-allergenic activity of n-3 PUFAs such as alpha-linolenic acid, eicosapentaenoic acid and docosahexaenoic acid in foods has also attracted attention Ž40., although convincing clinical evidence has not yet been provided Ž55.. Dihomo-gamma-linolenic acid ŽDGLA, C20:3v6., a precursor of arachidonic acid is the key substance in the synthesis of the LT3-series leukotrienes of low or anti-allergenic activity; the anti-allergenic action has been shown to originate from the competition between LT3-series and LT4-series leukotrienes Ž49.. It has also been postulated that in addition to the synthesis of LT4 , part of the activity would occur via the series 1 prostaglandins, particularly PGE 1 Ž47, 49.. The antiallergenic activity of n-3 PUFAs such as a-linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid has also been reported. Eicosapentaenoic acid is a key compound in the synthesis of the LT5 -series leukotrienes, and the allergic response is again believed to be restrained through the competition between LT5 and LT4 . Docosahexaenoic acid is not involved in the synthesis of leukotrienes. It is known, however, that n-3 PUFAs interfere with the arachidonic acid synthesis from n-6 PUFA linoleic acid and, thus, with the formation of various eicosanoids from arachidonic acid. In addition to the already described prostaglandins and leukotrienes, the lipid-based mediators include the platelet-activating factor ŽPAF. formed in the neutrophiles. The synthesis of PAF is stimulated with leukotrienes, and vice versa Ž56.. PAF activates the contraction of smooth muscle alpha cells, eosinophils 1 Ž8., neutrophils Ž58., and monocytes Ž69.. Furthermore, PAF accentuates vascular permeability, and its intervention with allergic diseases has been shown Ž60, 61.. It has also been suggested that the onset of an allergic reaction against rice is related to the uptake of lipid as an allergy response promoting agent and not an increase in the allergen uptake Ž62..

Watanabe et al. Ž64. have recently developed a method to eliminate the allergenicity of rice by soaking rice grain in the presence of a proteolytic enzyme, actinase, under vacuum at 37 8C for 24 h. The treatment breaks down the major allergenic globulin, and the radioallergosorbent test ŽRAST. Ž65. suggested no allergenicity in most cases. No allergic reaction was observed in six out of seven patients suffering from atopic dermatitis. The hypoallergenic rice has been submitted for approval as a physiologically functional food as defined by the Japanese Ministry of Health Ž18.. A hypoallergenic wheat flour has also been developed by the similar treatment of solubilized wheat proteins Ž66.. Methods to prepare hypoallergenic pasta-like noodles and bread from a batter made from collagenase treated wheat flour have also been reported Ž67.. Similar attempts have been reported to reduce the allergenicity of cow’s milk proteins, which are the most common antigens in infants Ž68, 69.. The most widely marketed hypoallergenic infant formulas are based on casein subjected to extensive enzymatic hydrolysis Ž70, 71., although occasional allergic reactions have been reported even when the degree of hydrolysis has been greater than 85% Ž72, 73.. Cordle et al. Ž73. hydrolyzed enzymatically casein and soy, for the potential use in hypoallergenic infant formulas, and concluded that both products appeared promising, with markedly reduced allergenicity. According to Siemensma et al. Ž74., most of the tested whey protein hydrolysate based hypoallergenic infant formulas contained no significant amounts of peptides of a molecular mass higher than 1500, although the quantity of free amino acids may vary from less than 20 mol% in the ‘third generation’ hypoallergenic formulae to higher than 70 mol% in the most hydrolyzed casein-based ‘first generation’ formulae. The presence of certain bitter peptides high in aromatic amino acids should be minimized in the hydrolysis. Clearly, both the type and size of the peptides in hypoallergenic infant formulas is of major importance, and should be taken into account when designing peptide-based hypoallergenic products. Quite recently Fukushima et al. Ž75. demonstrated that the consumption of hypoallergenic formula based on whey hydrolysates by pregnant and lactating mothers, and infants could be helpful in preventing allergy developments in infants, although the effect of special diets on the mother or infant in the subsequent development of atopic disease has still been questioned Ž1.. The onset of food allergies may also be reduced by removing or inactivating the allergy promoting agent, the practical use of allergy inhibitors, and by a combination of all three. It has been already reported that some foods have allergy inhibitory activity. This could be utilized in the production of low allergenic food Ž55.. The type I allergy is restrained by a number of phenolic compounds, which inhibit the discharge of a chemical mediator. For example, tea polyphenols which are typical antioxidants in food, promote the formation of IgA, restraining at the same time the formation of IgE Ž76. epigallocatechin gallate, which is the major

Production of Hypoallergenic Foods There is considerable interest in the reduction and elimination of the allergenic activity of foods during processing, and the development of either hypoallergenic foods, for example by enzymatic modification or genetic engineering, or substitute foods Ž63.. The most common method used to develop hypoallergenic foods is the decomposition or elimination of allergenic proteins. However, this procedure is not applicable to all foods Ž53.. Although a number of allergenic food proteins lose their activity by cooking or proteolysis, others are quite resistant to heat denaturation and enzymatic digestion.

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component of tea polyphenols has been shown to possess histamine blocking activity Ž77.. Polyphenolic compounds are believed to have anti-allergic activity by inhibiting lipoxygenase, the key enzyme in leukotriene synthesis. The development of hypoallergenic foods could be a solution to control allergic reactions against staple foods such as rice. This would be a major contribution to allergy prevention and health in general.

foods from standard food materials that are not easily recognized in their modified form by consumers allergic to food. The enzymatic hydrolysis of allergenic proteins has already been disscussed in the previous section. Another novel example is the fat substitute Simplesse W , formulated by the microparticulation of egg white and cow’s milk proteins Ž89.. The major allergens in the microparticulated products were the same as in the starting materials, and there was no evidence of any de no¨ o proteins in Simplesse W .

Effects of Processing on Food Allergens Genetic Engineering and Allergy Although more and more allergenic proteins are being isolated and identified from common foods, no universal chemical or structural characteristics have yet been identified. Food processing methods such as cooking are unlikely to destroy the allergenic activity of most foods. Many food allergens are water- or salt-soluble proteins or glycoproteins of relatively low molecular mass, and quite resistant against heat denaturation, although some heat-liable food allergens have also been identified Ž34.. The major allergens of cod, shrimp, egg, milk, peanuts, soybeans, wheat, rice, celery, tomato, mustard, hazelnut and almond are quite heat stable and resistant to processing and cooking Ž78.. Boiled eggs retain their allergenicity Ž79.. Even 45 min boiling does not completely eliminate the immunoreactivity of ovomucoid to human IgE Antibody. Both raw and roasted peanuts, as well as peanut butter, bind to peanut-specific IgE with an allergic response Ž80, 81.. Conversely, some patients who exhibit allergic symptoms to certain raw foods seem to tolerate boiled or cooked foods fairly well Ž82.. People allergic to raw salmon have been found to be able to tolerate canned salmon Ž83., and some reduction of the allergenicity of rice glutelin and globulin, and of soybean globulin by heat treatment has also been demonstrated Ž34.. Most studies concerning heat denaturation have been conducted using cow’s milk proteins. For example, heat treatment reduces but does not eliminate the allergenicity of whey proteins, and has little effect on the allergenicity of casein Ž84.. The allergens in many fresh fruits and vegetables, are quite sensitive to heat denaturation Ž85.. According to a recent report, the high allergenic activity of native celery roots is decreased markedly by thermal processing, although severe anaphylactic reactions may occur after ingestion of foods containing technologically processed or heated celery roots Ž81.. Although most food allergens are also resistant to digestion, fresh fruit allergens are relatively sensitive to proteolysis and digestion, and may cause oral allergy syndrome without other systemic effects Ž87, 88.. Thus, the canning of fruits or manufacture of jam and fruit preserves would probably eliminate allergenicity. Proteins are efficiently removed by the extraction of edible oils from oilseed such as peanut, rapeseed, soybean and sunflower seeds, rendering the resultant oils safe for consumption by allergic individuals Ž34.. New technologies have made it possible to design novel

More than 60 plants have already been genetically engineered, including a number of common crop plants such as corn Žmaize., soy, and wheat, for increased resistance to chemical herbicides, pests, diseases, and weather and soil conditions, and improved food processing characteristics Ž90]92.. The genetically modified organism will contain one or more foreign proteins as a result of gene transfer between unrelated species. This has raised concern regarding possible increased allergic reactions due to genetic engineering Ž93.. Astwood and Fuchs Ž94. have reviewed the current knowledge of the allergenicity of a number of transgenic food crops. Metcalfe et al. Ž95. have recently discussed in detail the assessment of the allergenic potential of genetically engineered plants, and Mendieta et al. Ž96. have reviewed the available in ¨ itro and in ¨ i¨ o tests for potential allergenicity in novel foods. When the gene donor source is a known allergenic food, the allergenicity of the transferred proteinŽs. can be readily determined. However, most transferred genes encode proteins of unknown allergenicity Ž97., and with the increasing incidence of allergies Ž98., carefully designed assessment of allergenicity is required to minimise risks to the consumer before transgenic foods are marketed Ž99.. An EU co-sponsored research project Žcontract no. AGRF-0039. was initiated in 1991 within the framework of the FLAIR ŽFood-Linked Agro-Industrial Reasearch. program for the molecularrbiological and toxiological characterization of tomatoes genetically modified by the introduction of a gene encoding the insecticidal crytal protein, CRYIAŽb. from Bacillus thuringiensis Ž98.. By 1995, the allergenic potency of the CYRIAŽb. protein had yet to be tested. On May 17 1994, the FDA completed its evaluation of the transgenic FLAVR SAVR tomato and the use of APHŽ3’r.II, a phosphorylating enzyme aminoglycoside39-phosphotransferase of the type commonly found in plants and animals, and concluded that the nonglycosylated APHŽ39r.II did not have homology with known allergens Ž99.. According to the FDA the possibility that proteins introduced into transgenic foods could cause allergic reactions in some individuals deserves special attention; the Japanese authorities hold similar views Ž100.. In November 1994, the decision by the FDA on the safety of the FLAVR SAVR tomato was made public. The agency’s Food Advisory Committee

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presented safety and nutritional information on a number of transgenic foods, including delayed-ripening tomatoes, insect pest-resistant corn and virus resistant potatoes, virus-resistant squash and glyphosate-tolerant soybean. Subsequently, the Food Advisory Committee agreed that there were no outstanding food safety issues associated with these products Ž101.. Shewry et al. Ž91. and Metcalfe et al. Ž95. concluded that genetically engineered crop plants should be regarded safe and could be introduced onto the market, with the same confidence as new plant varieties have been traditionally introduced after being developed by conventional breeding techniques. However, it is only natural to assume that genes transferred from allergenic sources encode allergens unless otherwise proven Ž102.. This has been demonstrated recently Ž103.; a gene from a Brazil-nut was intentionally transferred into a soybean to improve its nutritional quality Ž104.. It was shown that the transferred gene encoded a major Brazil-nut allergen and, consequently, the transgenic soybeans containing this allergen will not be marketed Ž38.. If the end-product used for human consumption is free of protein, the allergenic potential of the expressed protein is minimal or eliminated, as in peanut Ž105. sunflower Ž106. and soybean Ž107. oils, although coldpressed oil may contain residual protein Ž108.. The potential of genetic engineering in the production of hypoallergenic foods should not be overlooked. The production of hypoallergenic rice by genetic modification is a good example of how genetic engineering could benefit food allergy sufferers. If an allergen is a minor component in a food and is commonly recognized among patients, it may be possible to eliminate or reduce its level by novel processing or genetic engineering methods Ž21.. The use of recombinant DNA techniques in the identification and characterization of food allergens has already been of great value in the developing methods to reduce the incidence of food allergies Ž38..

in food processing and preparation can lead to contamination Ž80, 112.. Fatal food induced anaphylaxis has been reported, for example, from the ingestion of French fries prepared in fish-contaminated oil Ž13. and sausage containing 0.06% undeclared casein Ž19.. Severe anaphylactic reactions caused by complex foods containing leguminosae related thickeners, nuts, celery, spices, milk, eggs and fish have also been reported from a number of European countries Ž113.. Consequently, food processors should be cautious about sharing equipment, since even a trace contaminant can be fatal to a sensitive person. A severe allergic reaction has been reported, for example, of a child to peanut ‘dust’ on a flight when fellow passengers were opening their peanut packets Ž91.. Yunginger et al. Ž114. have reported several deaths due to unsuspected ingestion of allergenic food, often at food service establishments. Standardized methods for the determination of allergenic proteins, and an improved declaration of allergens was suggested as the result. Taylor and Cumming Ž31., and Sampson Ž2. have emphasized the importance of accurate food ingredient labelling in formulated foods to prevent the accidental ingestion of food allergens. According to Smith Ž115., an EC draft on allergen labelling is currently under preparation. At present, of the European member states, only Finland has specific legislative requirements for the labelling of potentially allergenic food ingredients. Finland requires at least almonds, barley, crustaceans, eggs, fish, milk, nuts, oats, peanuts, peas, rye, soybeans, and wheat to be declared. In Sweden there are guidelines to declare eggs, fish, gluten-containing grains, leguminous plants, nuts and sulphites present in the form of ‘margarine Žcontains milk.’, if the ingredient declared according to the EC compound ingredient rule is listed only with its name. Patients with a history of strong anaphylactic reactions to foods, insect bites, etc., should be advised to carry autoinjectable epinephrine Žadrenaline. ampoules Žeg. Epi-Pen. and antihistamine. Most children survive anaphylaxis when epinephrine is administered within 1 h Ž116.. Antihistamines and systemic corticosteroids may relieve some food allergic symptoms, but are not likely to markedly alter the course of food hypersensitivity Ž117.. Immunotherapy that contains a series of injections of the allergen, used successfully for respiratory allergies, has not been widely employed for food allergies Ž118.. Sugano Ž119. has recently reviewed the nutritional control of IgE production, the effects of dietary fat in relation to eicosanoid production, and the nutritional modulation of cytokine production. Peptide inhibitors of IgE binding to the Fc g R1 receptor have recently been described for the treatment of allergenic responses Ž120.. The frequency of food allergy is highest in the early childhood, and it has been estimated that up to 3% of children under the age of 6 years exhibit symptoms of food allergy Ž121.. The management of an infant who is allergic to cow’s milk can be a major problem Ž1.. For example, soy protein-based infant formulae are known to have caused similar clinical reactions to cow’s milk.

Treatment of Food Allergy Various aspects of food allergy and the therapy of food allergic disorders have been discussed by the IFT Expert panel on Food Safety & Nutrition Ž31. and recently reviewed by Sampson Ž109.. Once hypersensitivity to a food has been diagnosed, the only currently proven efficient treatment for allergic patients is the avoidance of the foods responsible for inducing allergic symptoms Ž110, 111.. In practice, this may sometimes be difficult due to exposure to hidden allergens Ž12, 86.. For example, celery powder, egg, milk powder, rice, seafood, and so on may be ‘concealed’ in prepared foods. Pollock-based surimi, for example, may be used in the production of imitation crustacean such as crab, and pork or beef substitutes may be used in pizza toppings. People may be exposed to cooking vapours, or infants may be sensitized to allergenic foods via their mother’s milk. Even the use of shared equipment

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in the food industry. Food Technology, 46, 153]156 Ž1992. 7 DEIBEL, K., TRAUTMAN, T., DEBOOM, T., SVEUM, W. H., DUNAIF, G., SCOTT, V. N. AND BERNARD, D. T. A comprehensive approach to reducing the risk of allergens in foods. Journal of Food Protection, 60, 436]441 Ž1997. 8 WEBER, R. S. Food additives and allergy. Annals of Allergy, 70, 183]190 Ž1993. 9 O’NEIL, C. E. AND LEHRER, S. B. Scientific status summary}Seafood allergy and allergens: a review. Food Technology, 49, 103]116 Ž1995. 10 YAMADA, K., TAKASUGI, M. AND SUGANO, M. Allergyregulating factors in food stuffs: hypoallergenic food and its prospects Žin Japanese..In: IKEZAWA, Z. ŽEd., Hypoallergenic Food and Its Prospects. Tokyo: CMC, pp. 83]90 Ž1995. 11 WATANABE, M. Hypoallergenic rice as a physiologically functional food. Trends in Food Science and Technology, 4, 125]128 Ž1996. 12 ANDRE, C., COLIN, L. AND CANCARCI, F. Role of new allergens and of allergens consumption in the increased incidence of food sensitizations in France. Toxicology, 93, 77]83 Ž1994. 13 HEFLE, S. L., NORDLEE, J. A. AND TAYLOR, S. L. Allergenic foods. Critical Re¨ iew of Food Science and Nutrition, 36, S69]S89 Ž1996. 14 MALMHEDEN, Y. I. Severe reactions Žin Swedish.. Var ˚ Foda, ¨ 48Ž2., 17 Ž1996. 15 SCHLOSS, O. M. A case of allergy to common foods. American Journal of Diseases of Children, 3, 342]362 Ž1912.; reprinted in Nutrition Re¨ iew, 41, 249]252 Ž1983. 16 PRAUSNITZ, C. AND KUSTNER, H. Studies on supersensitivity. Centralblatt fur ¨ Bakteriologie und Parasifenkunde 86, 160]169 Ž1921. 17 BURNET, F. M. The Clonal Selection Theory of Acquired Immunity. London: Cambridge University Press Ž1959. 18 ANON. Glossary of terms. Critical Re¨ iew of Food Science and Nutrition, 36 Ž1996. 19 HEFLE, S. The chemistry and biology of food allergens. Food Technology, 50Ž3., 86]92 Ž1996. 20 BUSH, R. K. AND HEFLE, S. L. Food allergens. Critical Re¨ iews of Food Science and Nutrition, 36, S119]S163 Ž1996. 21 MATSUDA, T. AND NAKAMURA, R. Molecular structure and immunological properties of food allergens. Trends in Food Science and Technology, 4, 289]293 Ž1993. 22 SAMPSON, H. A. AND METCALFE, D. D. Food Allergies. Journal of the American Medical Association 268, 2840]2844 Ž1992. 23 MEKORI, Y. A. Introduction to allergic diseases. Critical Re¨ iew of Food Science and Nutrition 36, S1]S18 Ž1996. 24 WUETRICH, B. AND ORTHOLANI, C. ŽEds. Highlights in Food Allergy, Proc. 16th Int. Symp. on Immunological and Clinical Problems of Food Allergy, Lugano, Switzerland, September 24]26, 1995. Monographs in Allergy, 32 Ž1996. 25 ORTHOLANI, C. AND PASTORELLO, E. A. ŽEds.. Study of Nutritional Factors in Food Allergies and Food Intolerances. Luxembourg: Office for Official Publications of the European Communities, EUR 16893, L-2985, 196 pp. Ž1997. 26 FURUKAWA, C. T. Non-immunologic food reactions that can be confused with allergy. Immunology and Allergy Clinics of North America 11, 815]818 Ž1991. 27 CLARKE, L., MCQUEEN, J., SAMILD, A. AND SWAIN, A. Dietitians association of Australia review paper. Australian Journal of Nutrition Dietetics, 53, 89]98 Ž1996. 28 ANDERSON, J. A. AND SOGN, D. D. ŽEds. Ad¨ erse Reactions to Foods, PHS-NIH Publication No. 84-2442. Milwaukee, Wisconsin: American Academy of Allergy and Immunology, pp. 1-6, Ž1984. 29 OTUKA, N. AND YAMASIRO, Y. Crisis mechanism of food allergy watched from alimentary canal. In: UENOKAWA, S. AND KONDO, N. ŽEds., Food Allergy Countermeasures

Although many children outgrow food allergies, mainly to cow’s milk and egg, by their third birthday, elimination diets may have to be continued for several months or even for life. Allergies to peanuts, tree nuts, fish and shellfish tend to be long lasting Ž121]123.. Coeliac disease and dermatitis herpetiformis are life-long hypersensitivities requiring the strict avoidance of gluten containing grains. Recent information suggests, however, that certain prophylactic treatments may be effective in preventing some food allergic disorders Ž124.. A novel potential approach in the management of food allergy has been suggested recently by Majamaa and Isolauri Ž125.. It was demonstrated that probiotic bacteria such as Lactobacillus GG may promote endogenous barrier mechanisms in patients with atopic dermatitis and food allergy, and by alleviating intestinal inflammation may act as a useful tool in the treatment of food allergy.

Conclusions Recent changes in eating habits and in the environment are thought to be connected to the recent rapid increase in food and other allergies. Described above is the current knowledge of food allergies, methods with which food allergy may be decreased, the current knowledge on the mechanisms of food allergy, antiallergenic factors in food, and the relationships between fatty acids and allergy. A number of unanswered questions remain, such as: Ži. the structure and function relationships of food allergens that guide allergic reactions; Žii. the mechanism of allergy prevention in healthy subjects; Žiii. the key issues regarding the mechanism of allergy generation and its inhibition; Živ. the prediction of the allergenicity of genetically engineered foods. These problems are closely related to immunology in general, and unless they are solved, allergy prevention and therapy will be difficult. Although a number of food allergens have already been isolated and characterized, the further identification of the causative allergenic molecules in foods would considerably contibute to the diagnosis and therapy of food allergies, and aid in the development of hypoallergenic foods and food processing.

References 1 ANDERSON, J. A. Allergic reactions to foods. Critical Re¨ iews of Food Science and Nutrition, 36, S19]S38 Ž1996. 2 SAMPSON, H. A. Food hypersensitivity: manifestations, diagnosis, and natural history. Food Technology, 46Ž5., 141]144 Ž1992. 3 EMMETT, S. E. The European Food Intolerance Databanks project. Trends in Food Science and Technology, 7, 313]315 Ž1996. 4 UENOKAWA, S. Allergy which originates in food, 1, congnition of food allergen by immune system Žin Japanese.. Kagaku to Seibutsu, 25, 734]738 Ž1987. 5 MEKORI, Y. A. Introduction to allergic diseases, Critical Re¨ iews of Food Science and Nutrition, 36, S1]S18 Ž1996. 6 LEHRER, S. B. AND O’NEIL, C. E. Occupational reactions

8

lwtrvol. 32 Ž1999 . No. 1

30 31

32

33 34 35

36 37

38 39 40

41

42

43 44

45 46

47

48 49 50

Handbook Žin Japanese.. Tokyo: Science Forum, pp. 52]59 Ž1996. WALTZER, M. Allergy of the abdominal organs. Journal of Laboratory and Clinical Medicine, 26, 1867]1877 Ž1941. TAYLOR, S. L. AND CUMMING, D. B. Food allergies and sensitivities. A scientific status summary by the Institute of Food Technologists’ Expert Panel on Food Safety & Nutrition. Food Technol., 39Ž9., 65]71 Ž1985. BRUJNZEEL-KOOMEN, C., ORTOLANI, C., AAS, K., , B., M ONERET B INDSLEV -JENSEN, C., B JORKSTEN ¨ VAUTRIN, D. AND W¨ URTRICH, B. Position paper: Adverse reactions to food. Allergy, 50, 623]630 Ž1995. WUETRICH, B. Food allergies and intolerances. Lebensmittelchemie, 50, 155]156 Ž1996. TAYLOR, S. L. AND LEHRER, S. B. Principles and characteristics of food allergens. Critical Re¨ iews of Food Science and Nutrition, 36, S91]S118 Ž1996.. SAMPSON, H. A. AND COOKE, S. Food allergy and potential allergenicity-antigenicity of microparticulated egg and cow’s milk proteins. Journal of the American College of Nutrition, 9, 410]417 Ž1990. METCALFE, D. D. Warning: eat, do not inhale. Allergy Proceeding, 11, 35]38 Ž1990. LEHRER, H. B., HORNER, W. E. AND RESSE, G. Why are some proteins allergenic? Implications for biotechnology. Critical Re¨ iews of Food Science and Nutrition., 36, 553]564 Ž1996. ASTWOOD, J. D. AND FUCHS, R. L. Preventing food allergy: Emerging technologies. Trends in Food Science and Technology, 7, 219]226 Ž1996. TAYLOR, S. L. Chemistry and detection of food allergens. Food Technology, 46Ž5., 146]148 Ž1992. MURAKAMI, H. AND UENOKAWA, S. Biophylaxis by food composition. In: Food Anaphylaxis Žin Japanese.. MURAKAMI, H. AND UENOKAWA, S. ŽEds., Tokyo; Kodansha Scientific, pp. 1]8 Ž1996. COOMBS, R. R. A. AND GELL, P. G. H. Classification of allergic reactions responsible for clinical hypersensitivity and disease. In: GELL, P. G. H., COOMBS, R. R. A. AND LACHMAN, P. J. ŽEds., Clinical Aspects of Immunology. Philadelphia: J. B. Lippincott, p. 761 Ž1975. KAMINOGAWA, S. Food allergy, oral tolerances and immunomodulation}their molecular and cellular mechanisms. Bioscience, Biotechnology, and Biochemistry, 60, 1749]1756 Ž1996. SAMPSON, H. A. AND BURKS, A. W. Mechanisms of food allergy. Annual Re¨ iew of Nutrition, 16, 161]177 Ž1996. COSTA, J. J., WELLER, P. F. AND GALLI, S. J. The cells of the allergic response; mast cells, basophils, and eosinophils. Journal of the American Medical Association, 278, 1815]1822 Ž1997. TORIL, S. Allergies and polyunsaturated fatty acid. Kensa to Kijutsu, 25, 879]882 Ž1997. HIGGS, G. A. HIGGS, E. A. AND MONACA, S. The arachidonic acid cascade. In: SAMMES, P. G. ŽEd., Comprehensi¨ e Medicinal Chemistry, Oxford: Pergamon Press, Vol 2, pp. 147]173 Ž1990. LANDS, W, E. M., LIBELT, B., MORRIS, A., KRAMER, N. C., PREWITT, T. E., BOWEN, P., SCHMEISSER, D., DAVIDSON, M. H. AND BURNS, J. H. Maintenance of lower proportions of Žn-6. eicosanoid precursors in phospholipids of human plasma in response to added dietary Žn-3. fatty acids. Biochimica Biophysica Acta, 1180, 147]162 Ž1992. SAMUELSON, B. Leukotrienes: Mediators of immediate hypersensitivity reactions and inflammation. Science, 220, 568]575 Ž1983. YAMADA, K., SUGANO, M. AND MATUO, T. Allergyregulating factors in foodstuffs and development of antiallergic foods. Up-to-date Food Processing, 32, 4]7 Ž1997. MONG, S., HOGABOOM, G. K., CLARKE, M. A. AND CROOKE, S. T. Molecular heterogeneity of leucotriene receptors. In: O’Brien, R. A. ŽEd., Receptor Binding in

51

52

53

54 55 56

57

58

59

60

61

62

63 64

65 66

67

68

9

Drug Research. New York: Marcel Dekker, pp. 205]234 Ž1986. HWANG, D., BOUDREAN, M. AND CHANMUGAM, P. Dietary linolenic acid and longer-chain n-3 fatty acids: comparison of effects on arachidonic acid metabolism in rats. Journal of Nutrition, 118, 427]437 Ž1988. NAKAMURA, N., HAMAZAKI, T., KOBAYASHI, M. AND YAZAWA, K. The effect of oral administration of eicosapentaenoic and docosahexaenoic acids on acute inflammation and fatty acid composition in rats. Journal of Nutritional Science and Vitaminology 40, 161]170 Ž1994. HASHIMOTO, A., KATAGIRI, M., TORIL, S., DAINAKA, J., ICHIKAWA, A. AND OKUYAMA, H.: Effect of the dietary alpha-linolenaterlinoleate balance on leukotriene production and histamine release in rats. Prostaglandins, 36, 3]16 Ž1988. KOSUNA, K. Anti-allergic action of perilla extract and its application to foods Žin Japanese.. New Food Industry, 34, 30]32 Ž1992. SUGANO, M. AND YAMADA, K. Trends of lower allergy food development Žin Japanese.. Food and Science, 34, 55]58 Ž1993. BILLAH, M. M., BRYANT, R. W, AND SIEGEL, M. I. Lipoxygenase products of arachidonic acid modulate biosynthesis of platelet-activating factor Ž1-O-Alkyl-2acetyl-sn-glycero-3-phosphocholine. by human neutrophils via phospholipase A 2 . Journal of Biological Chemistry, 260, 6899]6906 Ž1985. FUKUDA, T., AKUTU, K., NUMAO, T. AND MAKINO, S. Eosinophils and platelet - activating factor Žin Japanese.. In: WAKU, K. AND INOUE, K. ŽEds., Gendai Kagaku. Tokyo: Kagaku Dojin, Suppl. 17, pp. 108]114 Ž1989. SATOUCHI, K., ODA, S. AND SAITOU, K. Neutrophil, platelet activating factor Žin Japanese.. In: WAKU, K. AND INOUE, K. ŽEds., Gendai Kagaku. Tokyo: Kagaku Dojin, Suppl. 17, pp. 115]121 Ž1989. HAYASHI, H. AND KUDOU, I. Monocyte macrophage cell, platelet - activating factor Žin Japanese.. In: WAKU, K. AND INOUE, K. ŽEds., Gendai Kagaku. Tokyo: Kagaku Dojin, Suppl. 17, pp. 122]127 Ž1989. KASUYA, Y. Vascularity, platelet - activating factor Žin Japanese.. In: WAKU, K. AND INOUE, K. ŽEds., Gendai Kagaku. Tokyo: Kagaku Dojin, Suppl. 17, pp. 156]159 Ž1989. OISHI, S. Inflammatory reaction, platelet-activating factor Žin Japanese.. In: WAKU, K. AND INOUE, K. ŽEds., Gendai Kagaku. Tokyo: Kagaku Dojin, Suppl. 17, pp. 166]170 Ž1989. YAMADA, K. Accommodation of antibody formation by food compostition. In: Food Allergy Žin Japanese.. SUGANO, M. AND KISHINO, Y. ŽEds., supervised by Japan Society of Nutrition and Food Science, Tokyo: Koseikan, pp. 67]86 Ž1995. ITOH, Y. Current status of development of substitute, hypoallergenic and antiallergic foods for food allergy. Bio Industry, 13Ž2., 36]43 Ž1996. WATANABE, M., MIYAKAWA, J., IKEZAWA, Z., SUZUKI, Y., HIRAO, T., YOSHIZAWA. T. AND ARAI, S. Production of hypoallergenic rice by enzymatic decomposition of constituent proteins. Journal of Food Science, 55, 781]783 Ž1990. AAS, K. AND LUNDKVIST, U. The radioallergosorbent test with purified allergen from codfish. Clinical Allergy, 3, 255]261 Ž1973. WATANBE, M., SUZUKI, T., IKEZAWA, Z. AND ARAI, S. Controlled enzymatic treatment of wheat proteins for the production of hypoallergenic flour. Bioscience, Biotechnology, and Biochemistry, 58, 388]390 Ž1994. WATANBE, M., IKEZAWA, Z. AND ARAI, S. Fabrication and quality evaluation of hypoallergenic wheat products. Bioscience, Biotechnology, and Biochemistry, 58, 2061]2065 Ž1994. TOSSAVAINEN, O., HEIKONEN, M. AND LINKO, P. Effect

lwtrvol. 32 Ž1999 . No. 1

69

70 71 72 73

74

75

76 77 78

79 80

81 82

83

84 85 86

87

of processing on allergenic properties of milk proteins Žin Finnish.. Karjantuote, 66Ž3., 10]12 Ž1983. CHIANCONE, E. AND GATTONI, M. Selective removal of b-lactoglobulin directly from cow’s milk and preparation of hypoallergenic formulas: a bioaffinity method. Biotechnology and Applied Biochemistry, 18, 1]8 Ž1993. TAYLOR, S. L. Immunologic and allergic properties of cow’s milk proteins in humans. Journal of Food Protection, 49, 239]250 WAHN, U., WAHN, R. AND RUGO, E. Comparison of the residual allergenic activity of six different hydrolyzed protein formulas. Journal of Pediatrics, 121, S80]S84 BOCK, S. A. Probable allergic reaction to casein hydrolysate formula. Journal of Allergy and Clinical Immunology, 84, 272]277 Ž1989. CORDLE, C. T., MAHMOUD, M. I. AND MOORE, V. Immunogenecity evaluation of protein hydrolysates for hypoallergenic infant formula. Journal of Pediatric Gastroenterology and Nutrition, 13, 270]276 Ž1991. SIEMENSMA, A. D., WEIJER, W. J. AND BAK, H J. The importance of peptide lengths in hypoallergenic infant formulae. Trends in Food Science and Technology, 4, 16]21 Ž1993. FUKUSHIMA, Y., IWAMOTO, K., TAKEUCHI-NAKASHIMA, A., AKAMATSU, N., FUJINO-NUMATA, N., YOSHIKOSHI, M., ONDA, T. AND KITAGAWA, M. Preventive effect of whey hydrolysate formulas for mothers and infants against allergy development in infants for the first 2 years. Journal of Nutritional Science and Vitaminology, 43, 397]411 Ž1997. MAEDA-YAMAMOTO, M. Antiallergic action of tea and the utilization. Bio. Industry, 14Ž2., 41]47 Ž1997. OHSU, H., TAKEO, T., SUGIYAMA, K. AND YOKOTA, M. Studies on anti-allergy activities in tea. Fragrance Journal, 11, 50]53 Ž1990. VIETHS, S., AULEPP, H., BECKER, W.-M AND BUSCHMANN, L. Characterization of liable and stable allergens in foods of plant origin. In: Eisenbrand, G ŽEd.. Food Allergies and Intolerances. Weinheim VCH, pp. 130]149 Ž1996. GU, J., MATSUDA, T., AND NAKAMURA, R. Antigenicity remaining in boiled shell eggs. Journal of Food Science, 51, 1448]1450 Ž1986. NORDLEE, J. A., TAYLOR, S. L., JONES, B. T. AND YUNGINGER, J. W. Allergenicity of various peanut products as determined by RAST inhibition. Journal of Allergy and Clinical Immunology, 68, 376]382 Ž1981. BARNETT, D., BALDO, B. A. AND HOWDEN, W. E. H. Multiplicity of allergens in peanuts. Journal of Allergy and Clinical Immunology, 72, 61]68 Ž1983. KONDO, N., AGATA, H., FUKUTOMI, O., NISHIDA, T., KAMEYAMA, T., FUJII, H., HAYASHI, T., SHINBARA, M., YAMASAKI, M., UTSUMI, M., YANO, M AND ORII, T. Reduced responses of peripheral blood lymphocytes to heat-denatured food antigens in food-sensitive atopic dermatitis. Annals of Allergy, 70, 467]469 Ž1993. BERNHISEL-BROADBENT, J., STRAUSE, D., AND SAMPSON, H. A. Fish hypersensitivity. II. Clinical relevance of altered fish allergenicity caused by various preparation methods. Journal of Allergy and Clinical Immunology, 90, 622]627 Ž1992. LEE, Y. H. Food processing approaches to altering allergenic potential of milk-based formula. Journal of Pediatrics, 121, 847]851 Ž1992. DREBORG, S. AND FIUCARD, T. Allergy to apple, carrot and potato in children with birch pollen allergy. Allergy, 38, 146]149 Ž1983. JANKIEWICZ, A., BALTES, W., BOGL ¨ , K. W., DEHNE, L. I., JAMIN, A., HOFFMANN, A., HAUSTEIN, D. AND VIETHS, S. Influence of food processing on the immunochemical stability of celery allergens. Journal of Science and Food Agriculture, 75, 359]370 Ž1997. AMLOT, P. L., KEMENY, D, M., ZACHARY, C., PARKS, P.

LESSOF, M. H. Oral Allergy syndrome ŽOAS.: symptoms of IgE-mediated hypersensitivity to foods. Clinical Allergy, 17, 33]37 Ž1987. ORTOLANI, C., ISPANO, M., PASTORELLO, E., BIGI, A. AND ANSALONI, R. The oral allergy syndrome. Annals of Allergy, 61, 47]51 Ž1988. SAMPSON, H. A. AND COOKE, S. The antigenicity of microparticulated proteins: Simplesse W. Clinical and Experimental Allergy, 22, 963]969 Ž1992. DAY, P. R. Genetic modification of proteins in food. Critical Re¨ iews in Food Science and Nutrition, 36, S49]S67 Ž1996. SHREWRY, P. R., TATHAM, A. S., BARRO, F., BARCELO, P. AND LAZZERI, P. Biotechnology of breadmaking: unraveling and manipulating the multi-protein gluten complex. BiorTechnology, 13, 1185]1190 Ž1995. VASIL, V., SCRIVASTAVA, V., CASTILLO, A. M., FROM, M. E. AND VASIL, I. K. Rapid production of transgenic wheat plants by direct bombardment of cultured immature embryos. BiorTechnology, 11, 1553]1558 Ž1993. FRICK, O. L. The potential for allergenicity in transgenic foods. ACS Symposium Series, 605, 101]112 Ž1995. ASTWOOD, J. D. AND FUCHS, R. L. Allergenicity in foods derived from transgenic plants. Monographs in Allergy, 32, 105]120 Ž1996. METCALFE, D. D., ASTWOOD, J. D., TOWNSEND, R., SAMPSON, H. A., TAYLOR, S. L. AND FUCHS, R. L. Assessment of the allergenic potential of foods derived from genetically engineered plants. Critical Re¨ iews in Food Science and Nutrition, 36, S165]S186 Ž1996. MENDIETA, N. L. R., NAGY, A.-M. AND LINTS, F. A. The potential allergenicity of novel foods. Journal of the Science of Food and Agriculture, 75, 405]411 Ž1997. HOLGATE, S. T. AND CHURCH, M. K. ŽEds. Allergy. London: Gower Medical Publishing Ž1993. NOTEBORN, H. P. J. M., BIENENMANN-O’PLOUM, M. E., VAN DEN BERG J. H. J., ALINK, G. M., ZOLLA, I., REYNAERTS, A., PENSA, M. AND KUIPER, H. A. Safety assessment of the Bacillus thuringiensis insecticidal crystal protein CYRIAŽb. expressed in transgenic tomatoes. ACS Symposium Series, 605, 134]147 Ž1995. REDENBAUGH, K., HIATT, W., MARTINEAU, B. AND EMLAY, D. Determination of the safety of genetically engineered crops. ACS Symposium Series, 605, 72]87 Ž1995. TAKAHARA, R. Administrative oversight to ensure safety of biotechnologically produced foods in Japan. ACS Symposium Series, 605, 33]51 Ž1995. MARIANSKI, J. H. U.S. Food and Drug Administration policy for foods developed by biotechnology. ACS Symposium Series, 605, 12]22 Ž1995. NESTLE, M. Allergies to transgenic foods}questions of policy. New England Journal of Medicine, 334, 726]728 Ž1996. NORDLEE, J. A., TAYLOR, S. L., TOWNSEND, J. A., THOMAS, L. AND BUSH, R. K. Identification of a Brazil-nut allergen in transgenic soybeans. New England Journal of Medicine, 334, 688-692 Ž1996. ASTWOOD, J. D., LEACH, J. N. AND FUCHS, R. L. Stability of food allergens to digestion in ¨ itro. Nature Biotechnology, 14, 1269]1273 Ž1996. TALYOR, S. L., BUSSE, W. W., SACHS, M. I., PARKER, J. L. AND YUNGINGER, J. W. Peanut oil is not allergenic to peanut-sensitive individuals. Journal of Allergy and Clinical Immunology, 69, 373]381 Ž1981. HALSEY, A. B., MARTIN, M. E., RUFF, M. E., JACOBS, F. O. AND JACOBS, R, I. Sunflower oil is not allergenic to sunflower-sensitive individuals. Journal of Allergy and Clinical Immunology, 78, 408]415 Ž1986. BUSH, R. K., TAYLOR, S. L., NORDLEE, J. A. AND BUSSE, W. W. Soybean oil is not allergenic to soybean-sensitive individuals. Journal of Allergy and Clinical Immunology, 76, 242]247 Ž1985. AND

88 89 90 91

92

93 94 95

96 97 98

99

100 101 102 103

104 105

106

107

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108 YUNGINGER, J. Scientific Issues Related to Potential Allergenicity in Transgenic Food Crops ŽDocket 94N-0053.. Food and Drug Administration, Washington, D.C., U.S.A. Ž1994. 109 SAMPSON, H. A. Food allergy. Journal of the American Medical Association, 278, 1888]1894 110 BOCK, S. A., SAMPSON, H. A., ATKINS, F. M., ZEIGER, R. S., LEHRER, S. B., SACHS, M., BUSH, R. K. AND METCALFE, D. D. Double-blind, placebo-controlled food challenge ŽDBPCFC. as an office procedure: a manual. Journal of Allergy and Clinical Immunology, 82, 986]997 Ž1988. 111 BARNES-KOERNER, C. AND SAMPSON, H. A. Diets and nutrition. In Food Allergy: Ad¨ erse Reactions to Foods and Food Additi¨ es. METCALFE, D. D., SAMPSON, H. A. AND SIMON, R. ŽEds., Cambridge: Blackwell Scientific Publications, pp. 332]354 Ž1991. 112 GERN, J. E., YANG, E., EVCARD, H. M. AND SAMPSON, H. A. Allergic reactions to milk-contaminated ‘‘non-dairy’’ products. New England Journal of Medicine, 324, 976]979 Ž1991. 113 VIETHS, S., FISCHER, K., DEHNE, L. I., AULEPP, H., WOLLENBERG, H. AND BOGL ¨ , K. W. Bundesgesundheitsblatt, 37, 51]60 Ž1994. 114 YUNGINGER, J. W., SWEENEY, K. G., STRURNER, W. Q., GIANMANDREA, L. A., TEIGLAND, J. D., BRAY, M., BENSON, P. A., YORK, J. A., BIEDRZYCKI, L., SQUILLANCE, D. L. AND HELM, R. M. Fatal food-induced anaphylaxis. Journal of the American Medical Association, 260, 1450]1452 Ž1988. 115 SMITH, J. Allergens labelling. International Food Ingredients, Ž4., 12]13 Ž1997.

116 SAMPSON, H. A., MENDELSON, L. AND ROSEN, J. P. Fatal and near-fatal anaphylactic reactions to food in children and adolescents. New England Journal of Medicine, 327, 380]384 Ž1992. 117 SOGN, D. D. Medications and their use in the treatment of adverse reactions to foods. Journal of Allergy and Clinical Immunology, 78, 238]243 Ž1986. 118 SAMPSON, H. A. Food allergy and the role of immunotherapy. Journal of Allergy and Clinical Immunology, 90 151]152 Ž1992. 119 SUGANO, M. Nutrition and food allergies Žin Japanese.. Shokumotsu arerugi, 1995, 1]9 Ž1995. 120 JAMESON, B. A., SUTTON, B. J., MCDONNEL, J. M., KORNGOLD, R. AND NEAVIL, A. J. Peptide inhibitors of IgE binding to the Fc g R1 receptor. PCT ŽPatent Cooperation Treaty. International Application WO96, 0,1643 Ž1996. 121 BOCK, S. A. Prospective appraisal of complaints of adverse reactions to foods in children during the first 3 years of life. Pediatrics, 79, 683]688 Ž1987. 122 COLLIN-WILLIAMS, C. AND LEVY, L. D. Allergy to food other than milk. In: CHANDRA, R. K. ŽEd., Food Intolerance. New York: Elsevier, pp. 137]186 Ž1984. 123 SAMPSON, H. A. AND SCANLON, S. M. Natural history of food hypersensitivity in children with atopic dermatitis. Journal of Pediatrics, 115, 23]27 Ž1989. 124 SAMPSON, H. A. Food Allergies. Current Opinions in Gastroenterology. 11, 548]553 Ž1995. 125 MAJAMAA, H. AND ISOLAURI, E. Probiotics: A novel approach in the management of food allergy. Journal of Allergy and Clinical Immunology 99, 179]185 Ž1997.

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