Active formation of tolerance in case of allergy to cow's milk proteins

Food allergy is a potentially life-threatening condition in which there are no approved pathogenetic treatments other than elimination of the causal allergen and relief of acute allergic conditions. IgE- mediated form of food allergy remains a serious and growing problem worldwide. Its prevalence is steadily increasing, and is a severe psychosocial and economic burden for patients and their families. Cow's milk and products based on it are important components of a child's diet, which are introduced into the diet of children of the first year of life, but can cause allergic reactions. The traditional management of children with cow's milk allergy consists in prescribing an elimination dairy-free diet and a significant part of patients form tolerance to milk proteins by the age of 5 years. However, with persistent forms of allergy to cows milk proteins, the question is raised about the need for "active" tactics of patient management in order to form tolerance. Oral immunotherapy is a promising approach to the treatment of food allergies based on a gradual increase in the allergen taken, by analogy with standardized immunotherapy for respiratory allergens, until a maintenance dose is reached. Each stage of oral immunotherapy should be considered as a personalized therapy. This review contains an analysis of available studies on the effectiveness of oral immunotherapy in the treatment of allergy to cow's milk proteins.

Mechanisms of allergen-specific B cell tolerance in children with cow’s milk-oral immunotherapy and natural outgrowth of milk allergy

Antigen-specific memory B cells play a key role in the induction of immune tolerance to food allergens and clinical healing. Here, we characterized the role of allergen-specific B cells in immune tolerance induced by oral allergen-specific immunotherapy (OIT) and natural tolerance that developed in children who spontaneously outgrew cow’s milk allergy. Increased frequency of circulating milk allergen αS1-casein -specific B cells was observed after OIT and natural tolerance (NT). Milk desensitized subjects showed partial acquisition of tolerance phenotypic features induced tolerance, suggesting that desensitization is an earlier stage of tolerance. Immunoregulatory genes such as IL10RA and IGHG4 are significantly upregulated after OIT (desensitized and tolerance) versus NT. Secreted proteins from allergen-specific B cells revealed higher amounts of regulatory cytokines, IL-10 and TGF-β after OIT and NT. Taken together, allergen-specific B cells are essential elements in regulating food allergen tolerance in both OIT-received and naturally-resolved individuals.

Integrative Transcriptomics Reveals Activation of Innate Immune Responses and Inhibition of Inflammation During Oral Immunotherapy for Egg Allergy in Children

We previously reported the results of a randomized, open-label trial of egg oral immunotherapy (OIT) in 50 children where 44% were desensitized and 46% were partially desensitized after 8 months of treatment. Here we focus on cell-mediated molecular mechanisms driving desensitization during egg OIT. We sought to determine whether changes in genome-wide gene expression in blood cells during egg OIT correlate with humoral responses and the clinical outcome. The blood cell transcriptome of 50 children receiving egg OIT was profiled using peripheral blood mononuclear cell (PBMC) samples obtained at baseline and after 3 and 8 months of OIT. We identified 467 differentially expressed genes (DEGs) after 3 or 8 months of egg OIT. At 8 months, 86% of the DEGs were downregulated and played a role in the signaling of TREM1, IL-6, and IL-17. In correlation analyses, Gal d 1–4-specific IgG4 antibodies associated positively with DEGs playing a role in pathogen recognition and antigen presentation and negatively with DEGs playing a role in the signaling of IL-10, IL-6, and IL-17. Desensitized and partially desensitized patients had differences in their antibody responses, and although most of the transcriptomic changes were shared, both groups had also specific patterns, which suggest slower changes in partially desensitized and activation of NK cells in the desensitized group. OIT for egg allergy in children inhibits inflammation and activates innate immune responses regardless of the clinical outcome at 8 months. Changes in gene expression patterns first appear as posttranslational protein modifications, followed by more sustained epigenetic gene regulatory functions related to successful desensitization.

The clinical cross-reactivity and immunological cross-antigenicity of wheat and barley

Background: Some patients with a wheat allergy have been reported to show clinical cross-reactivity to barley. However, it is not clear whether the development of barley allergy in patients with a wheat allergy is due to cross-antigenicity between wheat and barley. In our study, we aimed to determine the clinical cross-reactivity and immunological cross-antigenicity of wheat and barley. Methods: We compared the results of barley oral food challenges (OFCs) before oral immunotherapy (OIT) for wheat with those after OIT in nine patients with a wheat allergy to estimate the clinical cross-reactivity of wheat and barley. Moreover, we performed enzyme-linked immunosorbent assay (ELISA) inhibition and immunoblotting inhibition using serum from seven patients allergic to wheat and barley. Results: Nine patients who had positive barley-OFC results performed before OIT for wheat were all negative on barley-OFC performed after OIT. In ELISA inhibition, preincubation of serum from patients allergic to wheat and barley with a high barley extract concentration inhibited binding of IgE to wheat extract by less than 10%. On the other hand, wheat and barley extracts equally inhibited binding to barley sIgE at high concentrations. In the immunoblotting inhibition test, the spots of wheat were inhibited but weakly by barley extracts, and most of the spots of barley were inhibited even by low concentrations of the wheat and barley extract. Conclusion: We showed that barley allergy associated with wheat allergy is caused by cross-reactivity from wheat. The OIT for wheat was one of the promising options for barley allergy.