Cow's milk challenge through human milk evokes immune responses in infants with cow's milk allergy.

OBJECTIVES: In order to measure the immune response evoked in breast-fed infants with cow's milk allergy (CMA) by cow's milk challenge through human milk, mothers were given increasing doses of cow's milk after they had been on a cow's milk elimination diet. Another objective was to study the secretion of beta-lactoglobulin (BLG) into human milk before and during milk challenge in relation to the appearance of symptoms in infants. STUDY DESIGN: Seventeen asymptomatic mothers who had infants with challenge-proven CMA and 10 asymptomatic mothers who had healthy infants were recruited. Infants ranged in age from 1.8 to 9.4 months. A solid-phase enzyme-linked immunoassay (ELISPOT) was used to assess the total number of immunoglobulin-secreting and specific antibody-secreting cells. Flow cytometry was used to enumerate different lymphocyte subpopulations among peripheral blood lymphocytes primed during provocation by cow's milk antigens. BLG levels were assessed in human milk before the challenge and 1, 2, 3, and 4 hours after the commencement of the challenge. RESULTS: All but one of the infants with CMA showed symptoms of CMA during cow's milk challenge through human milk. There was a significant rise in the total number of immunoglobulin-secreting cells in the IgA and IgG classes associated with a positive cow's milk challenge response, but the proportions of peripheral blood B cells bearing CD19, CD23, CD19 and 23, CD5, or CD19 and CD5 were comparable. BLG levels were comparable in both study groups. CONCLUSIONS: Most of the infants with CMA reacted to cow's milk challenge through human milk. Hypersensitivity reactions to food antigens through human milk may be more common than previously thought.     

Local immune response measured in blood lymphocytes reflects the clinical reactivity of children with cow's milk allergy

Study was made of immune responses in cow's milk allergy by a new immunoassay that measures total Ig-secreting cells and specific antibody-secreting cells during their maturation cycle in peripheral blood. These primed gut-associated lymphoid tissue-derived lymphocytes are assumed to reflect the intestinal immune responses. During diagnostic milk provocation, 15 patients had acute urticarial skin eruptions, eight patients had slow onset of eczema, and 15 showed symptoms from the gastrointestinal tract. A significant increase in IgM-secreting cells (means with 95% confidence intervals) from 382.2 (265, 552) to 621.4 (381, 1013)/10(6) cells, p less than 0.01, but not IgA- and IgG-secreting cells was associated with acute urticaria. In patients with eczematous skin eruptions and gastrointestinal symptoms, the response involved all these Ig isotypes. The magnitude of the postchallenge Ig-secreting cell responses in patients with gastrointestinal symptoms in the IgM class [from 657.9 (428, 1012) to 3544.0 (1696, 7406)/10(6) cells, p less than 0.001] and the IgA class [from 974.6 (590, 1610) to 2482.4 (1528, 4028)/10(6) cells, p = 0.001] significantly exceeded that of the patients with cutaneous symptoms. Notwithstanding the distinct increase in the total number of Ig-secreting cells, the specific antibody-secreting cell response specifically directed against beta-lactoglobulin and alpha-casein was small and inconsistent. These findings indicate that immune exclusion of milk antigens is defective in cow's milk allergy. The quality and extent of the response varied in the three reaction types, suggesting that different immunopathogenic mechanisms are operative in cow's milk allergy.     

A prospective study of humoral immune responses to cow milk antigens in the first year of life

Previous studies have shown that in cow milk allergy the specific immune response to dietary cow milk antigens is deficient. This study aimed at delineating the development of humoral immune response to cow milk antigens in healthy infants. Twenty-five healthy newborns were enrolled, and seen at scheduled visits at the ages of three, six and eleven months, and they formed two groups: those breastfed and those fed adapted cow milk formulae. The local immune response in the gut was approximated using the ELISPOT assay of circulating antibody secreting cells. At the age of three months, in the formula fed group, cells secreting specific IgA to cow milk antigens were detected despite low levels of IgA serum antibodies. The total number of IgA secreting cells increased with age (p = 0.001). The milk in the infant diet directly influenced this development so that the age related increase was significantly greater in the formula fed group (p = 0.04). The results indicate that diet has a significant effect on the developing immune system, and that healthy infants are able to respond in an antigen specific fashion to dietary antigens, which may be central in attaining clinical tolerance of such antigens.     

Manifestations of milk allergy in infancy: clinical and immunologic findings

In a study of the manifestations of cow milk allergy in 100 young children (mean age 16 months), 30 items of historical data and information relating to the effects of a standardized milk challenge were entered into a computer data base. Three clusters of patients were derived using a K-means algorithm. In group 1 were 27 patients with predominantly urticarial and angioedematous eruptions, which developed within 45 minutes of ingesting cow milk. They had positive skin test reactions to milk and elevated total and milk specific IgE serum antibody levels. In group 2, 53 patients had pallor, vomiting, or diarrhea between 45 minutes and 20 hours after milk ingestion. These children were relatively IgA deficient. The 20 patients in group 3 had eczematous or bronchitic or diarrheal symptoms; in 17 symptoms developed more than 20 hours after commencing milk ingestion. Of the patients in group 3, only those with eczema had a positive skin test reaction and elevated IgE antibodies to milk. The patients in group 3 were the most difficult to identify clinically; they had a history of chronic ill health, and symptoms developed many hours or days after commencing milk ingestion in the challenge situation. In view of the heterogeneous clinical and immunologic findings in our patients, it is unlikely that a single laboratory test will identify cow milk allergy in all susceptible patients.     

Immunologic disturbances in cow's milk allergy, 1: delayed maturation of suppressor activity

To assist in identifying pathogenetic mechanisms in different subtypes of cow's milk allergy (CMA), the function of immunoregulatory T-lymphocytes was studied. The study population consisted of 23 patients, mean [95% confidence interval] age of 25. 6 [19. 5, 33. 6] months, who had challenge-proven cow's milk allergy manifested with either skin (n=9) or gastrointestinal (n=14) symptoms; in addition, 13 age-matched disease controls were studied. Patients with challenge-proven CMA were rechallenged to establish whether they had acquired clinical tolerance to cow's milk. The suppressor activity of isolated lymphocytes was measured in vitro by a cell coculture at rechallenge and in 10/23 patients at diagnosis. At diagnosis, patients with CMA (n=10) showed a decreased mean [95% CI] suppressor activity, induced by either Concanavalin A, 7[-2, 15]%, or cow's milk, 3[-8, 14]% as compared with disease controls (n = 13), 19[15, 24]% and 24[17, 31]%; F = 7. 1, p = 0.004 and F = 6. 7, p = 0.005, respectively. At rechallenge the suppressor activity, induced both by Concanavalin A and cow's milk, reached the level of disease controls only in patients who had acquired clinical tolerance to cow's milk (n = 13/23), but not in those retaining CMA (n = 10/23). Our results indicate that the maturation of suppressor function is delayed in CMA, which might be of primary importance in the etiopathogenesis of CMA.     

Higher serum eosinophil cationic protein levels in children with cow's milk allergy

BACKGROUND: In the pathogenesis of cow's milk allergy, abnormal immunologically mediated reactions play a basic role. Eosinophil activation also participates in the development of several allergies. The purpose of this study was to characterize the degree of this activation by measuring the serum level of eosinophil cationic protein (sECP) and establishing whether it is a useful parameter in monitoring oral cow's milk allergy. METHODS: The sECP level of 35 patients with previously confirmed cow's milk allergy (mean age, 16 months) was evaluated using a fluoroimmunoassay before the cow's milk rechallenge test and at 2 hours and 24 hours after cow's milk challenge. RESULTS: Of the 35 children with previously confirmed cow's milk allergy, 10 had positive clinical reactions after the milk rechallenge test, whereas 25 children had no reaction. The median sECP level of all the patients before the challenge test was significantly higher (12.4 microg/L) than that of the control group (4.3 microg/L) (P < 0.05). Two hours after the challenge, the median sECP of all patients (9.4 microg/L) was lower than the starting values. The median sECP levels were higher in children with positive challenge test results at all time points. However, this difference was not statistically significant. CONCLUSIONS: The normalization of sECP level may indicate the cessation of the cow's milk allergy. Therefore, the measurement of sECP may be helpful in determining the optimal time in which to repeat the challenge test, when the result will more likely be negative. The significant decrease of the sECP level 2 hours after the beginning of milk challenge test may be explained by the fact that this protein is excreted into the intestinal lumen.     

Association of HLA-DQ7 antigen with cow milk protein allergy in Italian children

In this study we investigated the HLA association with cow milk allergy. Thirty-seven Italian children with cow milk allergy and 35 randomly selected age-matched healthy children as control group were included in the study. DNA typing was performed by restriction fragment length polymorphism (RFLP) technique. We show the first statistically significant positive association between the expression of the HLA-DQ7 antigen and cow milk allergy. Several immunological tests (skin prick test, RIA, radioallergosorb-ent test (RAST) and ELISA) were performed to evaluate the humoral immune responses of DQ7 positive and DQ7 negative allergic patients. Our results show that among the DQ7 positive patients the majority presented a high humoral response. Furthermore, the in vitro proliferative response of patients to the †-lactoglobulin antigen was performed to evaluate their cell-mediated immune response. We observed that the number of the nonre-sponders was higher in the DQ7 positive patients when compared to the DQ7 negative patients.
Our data indicate an association of HLA-DQ7 antigen with cow milk pro tein allergy and that the DQ7 positive patients had a prevalence of humoral rather than cellular responses.     

Recovery from milk allergy in early childhood: antibody studies

We assessed the relationships of clinical symptoms and serum antibody levels during follow-up of 47 patients, aged 3 to 66 months, who were shown by formal milk challenge to have cow milk allergy. Three groups of patients were identified. Group 1 patients (n = 15) were sensitized to IgE and responded rapidly to small volumes of milk with urticaria, an exacerbation of eczema, wheeze, or vomiting. In the second group (n = 24), symptoms of milk enteropathy (vomiting and diarrhea) developed between 1 and 20 hours after milk ingestion. In the group 3 patients (n = 8), coughing, diarrhea, eczematoid rashes, or a combination of these developed more than 20 hours after normal volumes of milk were given. Serum levels of IgG, IgA, IgM, and IgE and of milk-specific anti-cow milk antibodies of these isotypes were measured initially and then at a median follow-up time of 16 months (range 6 to 39 months). In this investigation, changes in these immunologic measures during the study period were related to whether or not clinical tolerance to cow milk was achieved. At follow-up, six patients from group 1, ten from group 2, and two from group 3 were milk tolerant. No consistent change in any of the immunologic measurements was associated with remission of the disease. These findings raise the question of whether acquisition of clinical tolerance to cow milk in cow milk allergy can be attributed solely to immunologic events.     

Use of infant formulas in infants with cow milk allergy

Allergic (immune-mediated) reactions to cow milk and other dietary proteins encountered during infancy are responsible for some of the adverse symptoms and syndromes observed in infants intolerant to cow milk, infant formulas and occasionally human milk. Iron deficiency anemia associated with gastrointestinal blood loss, protein losing enteropathy, enterocolitis, colitis, and malabsorption syndrome are examples of putative allergic reactions to dietary antigens which occur in infancy. A number of symptoms referable to the gastrointestinal tract such as, vomiting, colic and chronic non-specific diarrhea occur in infants both with and without immune-mediated reactions to dietary antigens. Verification of adverse reactions to dietary antigens, including allergic reactions, should be accomplished through the use of double-blind, placebo-controlled food challenge, with the dietary antigen to be tested presented in a liquid vehicle or, in older children, in capsule form. Approximately 8%–25% of children with immediate hypersensitivity to cow milk have been found to be allergic to soy products. Soy and other intact protein substitutes for cow milk, such as beef and lamb based formulas, have produced anaphylactic reactions both in human infants and in animal models. Hypoallergenic formulas should have a chemically modified protein base which demonstrates significant reduction in anti-genicity when tested in the laboratory both in vitro and in vivo. Such formulas should meet rigorous standards for hypoallergenicity in clinical testing in human allergic infants or infants at high risk for developing allergy before being labelled hypoallergenic.     

Safety of a new, ultrafiltrated whey hydrolysate formula in children with cow milk allergy: a clinical investigation

The purpose of this study was to determine whether a new ultrafiltrated whey hydrolysate infant formula, Profylac®, could be administered safely to children with cow milk protein allergy/intolerance. Profylac has a stated molecular weight of < 8 kD and at least 30, 000 times reduced antigenicity which is controlled by a combination of ELISA-techniques and immunochemical methods. The study comprised 66 children with cow milk protein allergy/intolerance diagnosed by controlled elimination/ challenge procedures. The children were aged 1 month-14. 5 years, median 1% years and 15 were below 1 year. Thirty-five of these children had proven IgE-mediated reactions (cow milk protein allergy). Sixty-one of the children had at least two different symptoms and 31 had concomitant allergies to other foods and/or inhalants. All 66 children underwent and tolerated open, controlled challenges with Profylac. A total of 64 children continued having Profylac daily for at least 3 months and 58 for at least 6 months after challenge. Nine of the children older than 1 year did not like the taste and only had Profylac in minor amounts. No side effects were registered. Fifteen of the infants were below 1 year of age, and this group was compared with an age matched group of 16 infants challenged with and fed an extensively hydrolysed casein hydrolysate, Nutramigen®. All the infants in these two groups accepted and tolerated Profylac and Nutramigen, respectively, and no side effects were registered. Among the 35 patients with IgE-mediated reactions 6% (2/35) had positive skin prick tests and 11% (3/28) had specific IgE class 2 against Profylac, 2 of the latter before intake of Profylac. None of the patients with non-IgE-mediated reactions had a positive skin prick test or specific IgE against Profylac. The study provides 95% confidence that this product is tolerated by at least 95% of children with cow milk protein allergy/intolerance and by 90% with IgE-mediated reactions. We conclude, that this ultrafiltrated whey hydrolysate is generally safe to feed to children with verified adverse reactions to cow milk protein, including children with IgE-mediated reactions. The taste of the product was widely accepted, also by older children.     

Defective tumor necrosis factor-α production in infants with cow’s milk allergy

As an aid to clarifying the role of immune mechanisms in the development of cow’s milk allergy (CMA) in suckling infants, we studied the capacity of peripheral blood mononuclear cells (PBMC) to produce tumor necrosis factor-α (TNF-α) in vitro. The study population consisted of 43 infants, aged 0.12–11.2 months; of these, 31 had challenge-proven cow’s milk allergy manifested with either skin or gastrointestinal symptoms or both. In addition, 12 healthy infants were studied as controls. The spontaneous, unstimulated and mitogen-induced production of TNF-α and interferon-γ (IFN-γ) by isolated peripheral blood leukocytes was evaluated. TNF-α and IFN-γ production of PBMC was significantly lower in infants with cow’s milk allergy than in healthy children. Our results indicate that, in infants with CMA, the function of TNF-α-producing cells is defective. This might disturb the development of oral tolerance and thereby lead to cow’s milk allergy. These results may help to clarify the etiopathology of CMA.     

Food allergy after liver transplantation in children: a prospective study

Food allergy has been increasingly reported in children who had orthotopic liver transplantation (OLT). We aimed to conduct a prospective study to investigate the prevalence of sensitizations and food allergy in pediatric OLT recipients. We also aimed to identify potential risk factors. The study group consisted of 28 children (14 male, 14 female, mean age 4.96 ± 0.76 yrs) who had OLT. Total eosinophil count (TEC), total IgE, and specific IgEs were studied before and 3, 6, 12 months after OLT. Six patients (21%) developed multiple food allergies. Mean age of six patients at OLT who developed food allergy was younger compared to the non‐food allergy group (10.2 months vs. 68.9 months, p < 0.05). Food allergy has been developed within 1 yr in 5, and in 20 months in one patient after OLT. All six patients had cow’s milk and egg allergy after OLT. Five children developed wheat, one children developed lentil and another one developed peach allergy in addition to cow’s milk and egg allergy. Out of six food‐allergic patients after OLT, four children developed Epstein–Barr virus (EBV) infection prior to food allergy. Before OLT, TECs and total IgE levels were not differed among food allergic and non‐food allergic patients (p > 0.05). Mean of TECs were significantly higher in food allergic group compared to non‐food allergic group at each time point after OLT (p < 0.05). Though statistically insignificant, mean of total IgE levels were also higher in the food allergic group (p > 0.05). These findings suggest that food allergy should be considered after OLT in patients who are younger than 1 yr of age, who developed hypereosinophilia, high total IgE levels or EBV viremia.     

Bone mineral status in children with cow milk allergy

To investigate bone mineral status in children with verified cow milk allergy for more than 4 yr compared with a large reference population of 343 local healthy controls. Whole body bone mineral content (BMC), projected bone area and bone mineral density (BMD) were determined by dual energy x-ray absorptiometry in nine children (8-17 yr old, one girl and eight boys). All children had cow milk allergy for more than 4 yr. All children had asthma and was treated with corticosteroids. BMC and BMD were reduced for age (p < 0.01). Height for age was significantly reduced (p < 0.01), indicating 'short' bones. BMC for bone area was borderline reduced (p = 0.05), indicating reduced bone mineralization. The growth of the children was reduced compared with there parents and siblings (p < 0.01), and the bone age was retarded (mean 1.4 yr, p < 0.01). Calcium consumption calculated from food intake was about 25% of the recommended. All laboratory tests were normal. Short bones were the main reason for reduced BMC and BMD for age in children with cow milk allergy, but a borderline low BMC for bone area indicated reduced bone mineralization of the bones. A supplementation of calcium to children with cow milk allergy is recommended.     

Lessons from the clinical course of IgE-mediated cow milk allergy in Israel

Cow milk and milk products are the most common food products consumed in Israel; rates of allergy to cow milk exceed those of peanuts in infants and children. The aim of the present study was to evaluate retrospectively the clinical features and natural course of immunoglobulin (Ig) E-mediated cow milk allergy (CMA) in Israel. Data of children diagnosed with CMA from 1995 to 2003, were collected regarding age at first and most recent reactions, symptoms and signs, family history of atopy, other allergic diseases, emergency department visits, hospitalizations, and treatment. Patients with transient CMA were compared to those with persistent CMA (> or =3 yr old). The study group consisted of 105 patients, 43 with transient CMA (age range: 0.48-11 yr). The remaining 62 patients (age range: 3-16.5 yr) did not achieve tolerance to cow milk during the follow-up period. No differences were found between the groups in mean age and symptoms and signs at the first allergic reaction and family history of atopy. Patients with persistent CMA had a higher rate of asthma than patients with transient CMA (61.2% vs. 18.6%, p < 0.001). Fifty patients with persistent CMA had 137 subsequent allergic reactions after diagnosis, 25% of the reactions were due to oral milk challenge at the clinic and 75% due to accidental exposure, of which 13% required an emergency department visit and 8%, hospitalization. Only 19% of the reactions were treated with epinephrine injection. In conclusion, in our experience, less than half of the children diagnosed with IgE-mediated CMA during 9 yr, outgrew it. The patients with persistent CMA have a higher prevalence of asthma compared with the general population or to children with transient CMA. The high number of recurrent allergic reactions due to accidental exposure and the low rate of epinephrine usage in these patients point to a need for better education of patients and their families.     

Acquired carbohydrate intolerance and cow milk protein-sensitive enteropathy in young infants

Sixty infants with acquired carbohydrate intolerance, 19 with protracted diarrhea, and 41 with features indistinguishable from acute infectious enteritis, were maintained on a lactose-free and cow milk protein-free formula for about eight weeks, after which jejunal biopsies were performed before and after oral provocation with cow milk protein. Following provocation, 43 infants showed mucocal abnormalities associated with marked reduction in the levels of all three disaccharidases. In one infant, mucosal change was unaccompanied by enzyme depletion. Six infants had enzyme depletion without visible mucosal changes. In ten infants the intestinal mucosa remained normal and there was no consistent pattern of change in the enzyme levels. The findings suggest that cow milk protein has a deleterious effect on the small bowel mucosa of young infants recovering from enteritis and may be an important contributing cause of acquired carbohydrate intolerance in these infants. In the management of young infants with acquired carbohydrate intolerance both the offending sugar and protein should be excluded.     

Food intolerance and food allergy in children: a review of 68 cases.

The clinical and laboratory features of 68 children with food intolerance or food allergy are reviewed. Young children were affected the most with 79% first experiencing symptoms before age 1 year. Forty-eight (70%) children presented with gastrointestinal symptoms (vomiting, diarrhoea, colic, abdominal pain, failure to thrive), 16 (24%) children with skin manifestations (eczema, urticaria, angioneurotic oedema, other rashes), and 4 (6%) children with wheeze. Twenty-one children had failed to thrive before diagnosis. A single food (most commonly cows'' milk) was concerned in 28 (41%) cases. Forty (59%) children had multiple food intolerance or allergy; eggs, cows'' milk, and wheat were the most common. Diagnosis was based on observing the effect of food withdrawal and of subsequent rechallenge. In many children food withdrawal will mean the use of an elimination diet which requires careful supervision by a dietician. Laboratory investigations were often unhelpful in suggesting or confirming the diagnosis.     

The pendulum between food protein-induced enterocolitis syndrome and IgE-mediated milk allergy

The transition from milk protein-induced enterocolitis syndrome to IgE-mediated milk allergy is uncommon. Herein, we describe three infants that suffered from recurrent vomiting and restlessness in response to cow's milk formula with negative skin prick to milk and therefore diagnosed as milk protein-induced enterocolitis syndrome. After recovering and reintroducing cow's milk formula, they developed disseminated urticaria and positive skin prick test to cow milk compatible with IgE-mediated milk allergy. CONCLUSION: An infant that recovers from cow milk food-induced enterocolitis syndrome might develop afterward IgE-mediated cow milk allergy.     

Lymphocyte response to cow's milk proteins in patients with cow's milk allergy: relationship to antigen exposure

The cellular immune response to cow's milk was measured in patients with challenge-proven cow's milk allergy (CMA), manifested with either gastrointestinal or skin symptoms. After 2–4 weeks on milk elimination, 44 children, mean (SD) age 15.7 (9.4) months, were challenged, and cow's milk-induced lymphocyte transformation was measured before the clinical challenge (Day 1) and / or one week later (Day 8). During the clinical challenge period, 17 (39%) patients showed gastrointestinal reactions, 9 (20%) had urticarial or eczematous skin eruptions, and 18 (41%) were negative to challenge. On Day 1, the mean [95% confidence interval] stimulation index for lymphocytes in patients manifesting CMA with gastrointestinal symptoms, 2.60 [1.60, 4.10], was significantly higher than that in patients with skin symptoms, 1.15 [0.60, 2.30], or patients with negative clinical challenge, 0.83 [0.64, 1.08], F = 9.0, p = 0.001. After the clinical challenge (Day 8), this cow's milk-induced lymphocyte proliferation response was abrogated. At the same time, CMA patients evidenced a significantly higher spontaneous lymphocyte proliferation response in RPMI medium-containing control cultures than those with negative clinical challenge. We conclude that in patients with CMA, the number of circulating cow's milk-sensitized lymphocytes is depleted or their function is impaired after clinical exposure to cow's milk antigens.     

Low colostral IgA associated with cow's milk allergy.

During a nutritional study of 198 infants, seven became allergic to cow's milk. The seven infants showed acute cutaneous manifestations during cow's milk challenge tests in hospital and six had increased levels of IgE cow's milk-specific antibodies. Neither in the development of the levels of immunoglobulins G, A and M, nor in that of the cow's milk-specific antibodies of these isotypes did these seven patients differ from the remaining infants. Beta-lactoglobulin content and levels of cow's milk-, and beta-lactoglobulin-specific antibodies and of immunoglobulins A, G and M were measured in samples of colostrum and milk from the mothers of the seven infants with cow's milk allergy and from a comparison group (non-atopic mothers of non-atopic infants). The milk of the mothers whose infants became allergic to cow's milk contained less IgA through the lactation: 95% confidence intervals of the groups did not overlap. The difference was most marked in the colostrum. All other measurements were similar in the two groups. This suggests that an infant is more likely to develop cow's milk allergy if the mother's colostrum had a low total IgA content.     

Development of natural tolerance and induced desensitization in cow’s milk allergy

Cow’s milk allergy (CMA) affects 2–3% of infants. It resolves in the great majority spontaneously during childhood. CMA encompasses a spectrum of clinical and immunologic characteristics. Non‐IgE‐mediated allergy typically resolves earlier than IgE‐mediated allergy. The most documented prognostic characteristic is that intense‐specific IgE response predicts persistence of CMA. Low serum levels of cow’s milk (CM)‐specific IgG4 are also associated with persistent CMA. Natural development of tolerance involves an immunologic shift where Th2 responses diminish, and Th1 as well as T regulatory cell responses strengthen. Accordingly, specific IgE levels decrease and specific IgG4, possibly also IgA, levels increase in serum. Specific oral immunotherapy (OIT) with CM induces desensitization in most cases where spontaneous recovery has not yet occurred. Data on long‐term tolerance induction are still scarce. According to current research data, the immunologic changes induced by OIT resemble those seen during natural development of tolerance.