Blocked IgE-mediated allergen presentation plays role in cow’s milk oral immunotherapy

Key takeaways:

• Researchers observed an increase in total IgE levels and decreases in cow’s milk sIgE, specifically IgA and IgG4 levels, 2 months after the maintenance phase of OIT.
• OIT had a 100% clinical response rate.
• FoxP3 mRNA expression among patients on immunotherapy was similar to those patients who developed natural tolerance.

OIT for cow’s milk allergy may succeed when IgE-mediated allergen presentation is blocked due to a blockage of antibodies, according to a study published in Annals of Allergy, Asthma & Immunology.

Treatment success also may be due to markedly increased IL-10 and transforming growth factor (TGF)-beta cytokine response as well as T regulatory (Treg) cell function, Nuren Cigerci Günaydin, MD, of the division of pediatric allergy and immunology, department of pediatrics, faculty of medicine, Namik Kemal University, Tekirdag, Turkey, and colleagues wrote in the study.

The study population and administration

The prospective observational cohort study evaluated 57 children with IgE-mediated cow’s milk allergy and 18 healthy similarly aged children who had no allergic symptoms and who had not been sensitized to cow’s milk. Also, 49 (63.6%) of the participants were girls, and the mean age of the cohort was 42.6 ± 39 months (range, 6-201).

The patients with cow’s milk allergy included 19 who received OIT because they faced challenges with avoidance measures, 20 patients who continued with avoidance measures, and 20 who had developed a tolerance to cow’s milk.

Symptoms among the 39 participants on OIT and avoidance measures at presentation included skin eruption (100%; n = 39), respiratory distress (15.3%; n = 6) and vomiting (10.2%; n = 4) within 2 hours of ingesting milk.

Comorbidities among these patients included atopic dermatitis (66.6%; n = 26), asthma (10.2%; n = 4) and allergic rhinitis (10.2%; n = 4), with two patients (5%) reporting a history of anaphylaxis after exposure to cow’s milk.

Oral food challenges had a median cumulative provocative dose of 6 mL (range, 0.5-48). Also, all the patients in the OIT group and two in the elimination group developed a tolerance to 200 mL of cow’s milk after 6 months of treatment.

The up-dosing phase had a median duration of 16 ± 4 weeks (range, 10-42). Nine patients (47.3%) experienced 36 adverse reactions during OIT, including 17 mild and eight moderate reactions, that all occurred in the hospital.

Reactions included respiratory distress (35.2%; n = 6), which was controlled with oral antihistamines; localized urticaria (29.4%; n = 5), which was controlled with oral antihistamines, steroids and inhaled beta-2 agonists; vomiting (11.7%; n = 2); and diarrhea (5.8%; n = 1). There were no cases of anaphylaxis.

There were no differences in median beta lactoglobulin (BLG)-sIgG4 or casein (CAS)-sIgG4 levels between the four groups at the beginning of the study, although the healthy control group had higher levels of median BLG-sIgA and CAS-sIgA.

The study results

After 6 months, the OIT and avoidance groups had increases in total IgE levels, the avoidance group had a decrease in cow’s milk sIgE levels, and the OIT group had significant increases in BLG-sIgA, CAS-sIgA, BLG-sIgG4 and CAS-sIgG4 levels.

CD4+CD25+FoxP3+Treg cell percentages included 2.5% before therapy and 2.8% after 6 months in the OIT group, 3% before therapy and 2.6% after 6 months in the avoidance group, 3.1% in the tolerance group and 3.1% in the healthy control group. The researchers did not consider these differences between groups to be significant.

Similarly, the researchers did not find any significant differences between the groups in IL-2 response without stimulation and polyclonal stimulation, although the avoidance group had higher IL-2 response with BLG stimulation.

Each group saw increases in IL-2 cytokine levels with polyclonal stimulation compared with unstimulated blood, with decreases with beta lactoglobulin stimulation compared with phytohemagglutinin (PHA) stimulation and basal levels.

Also, there were no differences in IL-10 responses without stimulation, with polyclonal stimulation or BLG stimulation. Each group saw increases in IL-10 levels with polyclonal stimulation compared with unstimulated blood and decreases with BLG compared with PHA stimulation and basal levels.

All the groups had similar TGF-beta responses without stimulation, with polyclonal stimulation and with BLG stimulation. TGF-beta levels increased in all groups with polyclonal stimulation and beta-lactoglobulin compared with unstimulated blood, but the researchers did not consider this change to be statistically significant.

The researchers also did not detect any significant IL-4 production in peripheral blood in response to BLG or PHA, nor were there any significant differences in basal cytokine levels in unstimulated blood compared with the beginning of therapy for the OIT and avoidance groups.

Further, there were no significant changes in IL-2 responses with BLG in the OIT and avoidance groups. However, the OIT group did experience an increase in IL-10 response (292 ± 213 pg/mL [3-808]; P = .04) but the avoidance group did not.

The OIT and avoidance groups did not experience any significant changes in IL-13 responses with BLG. Although TGF-beta responses with BLG increased for both groups compared with pretreatment levels, the researchers did not think these increases were statistically significant either.

Expression levels of the FoxP3 gene included a 1.23 mean ± 0.19 standard error mean (SEM) before therapy and 0.91 mean ± 0.2 SEM after 6 months for the OIT group, 1.28 mean ± 0.27 SEM before therapy and 1.45 mean ± 0.29 SEM after 6 months for the avoidance group, 0.39 mean ± 0.09 SEM in the tolerance group and 1.01 mean ± 0.23 SEM in the healthy control group.

The tolerance group experienced a 2.5-fold decrease in FoxP3 expression compared with the healthy control group. The researchers also found a significant difference in FoxP3 changes between the tolerance group and the OIT and avoidance groups after 6 months (P < .05).

The changes in FoxP3 expression were 1.24 times higher than the changes in the healthy group before therapy and 1.08 times lower after 6 months, but the researchers did not believe these differences were significant.

Participants who were desensitized to cow’s milk had a statistically significant positive correlation with TGF-beta and IL-10 cytokine concentrations and pretreatment and posttreatment FoxP3 messenger RNA (mRNA)-FoxP3 flow cytometric expressions.

Also, the avoidance group had significant positive correlations with TGF-beta concentrations and pretreatment (Spearman rank correlation = 0.54; P = .014) and posttreatment (Spearman rank correlation = 0.725; P = .002) FoxP3 mRNA-FoxP3 flow cytometric expressions.

The avoidance group experienced a significant positive correlation in its pretreatment FoxP3 mRNA increase and pretreatment TGF-beta(basal) as well (Spearman rank correlation = 0.836; P = .01).

Conclusions

Though the underlying mechanism of desensitization in OIT remains not entirely known, the researchers said their findings indicate that the response of allergen-specific antibodies may be important.

Specifically, patients who received OIT experienced significant production of blocking antibodies, suggesting that the blocking antibody response may be important to the treatment.

Also, the simulation of Treg cells may contribute to the reestablishment of clinical tolerance during OIT, the researchers said, adding that studies investigating the role and interaction of Tr1 and Br1 cells in how OIT works may be needed.