The WHO refers to human milk as the nutritional gold standard for term infants. Human milk contains many immunomodulatory compounds, including oligosaccharides. Human-milk oligosaccharides can serve ...as prebiotics because the nondigestible oligosaccharides present in human milk show a clear bifidogenic effect on the gut microbiota. Dietary oligosaccharide structures that have prebiotic effects similar to human-milk oligosaccharides include galacto-oligosaccharides, fructo-oligosaccharides, and pectin-derived acidic oligosaccharides. Both animal studies and human clinical trials showed that dietary intervention with these dietary oligosaccharides in early life could lead to the prevention of atopic dermatitis, food allergy, and allergic asthma. The immune-modulating effects of these oligosaccharides are likely assisted via alteration of the intestinal microbiota or in a microbiota-independent manner by direct interaction on immune cells or both. In this review, an overview of the prebiotic role of dietary oligosaccharides on the microbiota and the microbiota-independent immune modulation by these prebiotics is provided. In addition, recent publications that report on the pathways by which the oligosaccharides might exert their direct immunomodulatory effect are summarized.
Serum biomarkers for allergy in children Knipping, Karen; Knippels, Léon M.J.; Dupont, Christophe ...
Pediatric allergy and immunology,
March 2017, Letnik:
28, Številka:
2
Journal Article
Recenzirano
Odprti dostop
A large number of studies investigating various biomarkers for allergy have been published over the past decades. The aim of this review was to evaluate these biomarkers on their diagnostic and/or ...predictive value. To this date, no single or specific biomarker for allergy has been identified. As allergy is not one disease, but a collection of a number of allergic conditions, it is more plausible a combination of clinical history, clinical readouts, and diagnostic markers will be needed.
To cite this article: van Esch BCAM, Schouten B, de Kivit S, Hofman GA, Knippels LMJ, Willemsen LEM, Garssen J. Oral tolerance induction by partially hydrolyzed whey protein in mice is associated ...with enhanced numbers of Foxp3+ regulatory T‐cells in the mesenteric lymph nodes. Pediatr Allergy Immunol 2011: 22: 820–826.
Background: Hypoallergenic formulas are considered a good option for infants at risk for cow’s milk allergy. The aim of this animal study was to investigate whether whey hydrolyzates (WH) have the capacity to induce oral tolerance to whey.
Methods: Whey, partial or extensive WH was given via gavages to naïve mice prior to oral whey sensitization using cholera toxin as an adjuvant. The acute allergic skin response, mouse mast cell protease‐1 (mMCP‐1), whey‐specific IgE, IgG1 and effector Th2‐cells, Th1‐cells, and Foxp3+ regulatory T‐cells were determined in the mesenteric lymph nodes (MLN). MLN cells from tolerized mice were adoptively transferred to naïve recipient mice prior to whey sensitization.
Results: In contrast to the extensive WH, pre‐treatment of naïve mice with whey or partial WH reduced the acute allergic skin response and mast cell degranulation after whey challenge. However, only treatment with whey prevented the generation of serum‐specific IgE/IgG1. In partial WH tolerized mice, Foxp3+ regulatory T‐cell numbers in the MLN were increased compared to whey‐sensitized mice. Both whey and partial WH treatment showed a tendency toward a decreased number of effector Th2‐cells. Transfer of MLN cells from tolerized mice protected recipient mice from developing an acute allergic skin response.
Conclusion: These results show that partial WH with limited sensitizing properties reduced the effector response upon whey challenge. This effect is transferable using MLN cells and was associated with enhanced Foxp3+ regulatory T‐cell numbers in the MLN. Partial WH retained the capacity to induce active immune suppression in mice which may be relevant for allergy prevention.
Oral immunotherapy (OIT) is a promising therapeutic approach to treat food allergic patients. However, concerns with regards to safety and long-term efficacy of OIT remain. There is a need to ...identify biomarkers that predict, monitor and/or evaluate the effects of OIT. Here we present a method to select candidate biomarkers for efficacy and safety assessment of OIT using the computational approaches Bayesian networks (BN) and Topological Data Analysis (TDA).
Data were used from fructo-oligosaccharide diet-supported OIT experiments performed in 3 independent cow's milk allergy (CMA) and 2 independent peanut allergy (PNA) experiments in mice. Bioinformatical approaches were used to understand the data structure. The BN predicted the efficacy of OIT in the CMA with 86% and indicated a clear effect of scFOS/lcFOS on allergy parameters. For the PNA model, this BN (trained on CMA data) predicted an efficacy of OIT with 76% accuracy and shows similar effects of the allergen, treatment and diet as compared to the CMA model. The TDA identified clusters of biomarkers closely linked to biologically relevant clinical symptoms and also unrelated and redundant parameters within the network.
Here we provide a promising application of computational approaches to a) compare mechanistic features of two different food allergies during OIT b) determine the biological relevance of candidate biomarkers c) generate new hypotheses to explain why CMA has a different disease pattern than PNA and d) select relevant biomarkers for future studies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary
Background
Failure to induce oral tolerance may result in food allergy. Hydrolysed cow's milk‐based infant formulas are recommended in subjects with a high risk of developing allergic ...disease. Presentation of T cell epitopes is a prerequisite to generate regulatory T cells that could contribute to oral tolerance.
Objective
To investigate whether a specific hydrolysed whey‐based infant formula contains peptides that function as T cell epitopes to support the development of oral tolerance to whey.
Methods
First, a novel liquid chromatography‐mass spectrometry (LC‐MS) method was developed to characterize β‐lactoglobulin‐derived peptides present in a specific infant formula with a focus on region AA#13‐48 of β‐lactoglobulin, which has previously been described to contain T cell epitopes with tolerogenic potential. Second, the formula was subjected to the ProImmune ProPresent® antigen presentation assay and MHC class II binding algorithm to identify relevant HLA‐DRB1‐restricted peptides. Third, identified peptides were tested on human cow's milk protein‐specific T cell lines to determine T cell recognition.
Results
Thirteen peptides of minimal 9AAs long that overlap with AA#13‐48 of β‐lactoglobulin were identified. Six of them were found across all batches analysed. It was further confirmed that these peptides were processed and presented by human dendritic cells. The identified HLA‐DRB1‐restricted peptides were correlated to AA#11‐30 and AA#23‐39 of β‐lactoglobulin. Importantly, the proliferation assay showed that the synthetic peptides were recognized by cow's milk protein‐specific T cell lines and induced T cell proliferation.
Conclusion and Clinical Relevance
This study demonstrates that the tested hydrolysed infant formula contains functional HLA‐DRB1‐restricted T cell epitopes, which can potentially support the development of oral tolerance to whey.
Cow milk allergy is the most common food allergy in children. So far, no effective treatment is available to prevent or cure food allergy. The purpose of this study was to compare effects of dietary ...supplementation with a prebiotic mixture (Immunofortis), a probiotic strain Bifidobacterium breve M-16V, or a synbiotic diet combining both on the outcome of the allergic response when provided during oral sensitization with whey in mice. Mice were fed diets containing 2% (wt:wt) Immunofortis and/or the B. breve M-16V (n = 6/group). The acute allergic skin response was determined by measuring ear swelling. Antigen-induced anaphylaxis was scored. Furthermore, whey-specific serum immunoglobulins and mouse mast cell protease-1 (mMCP-1) were determined. In mice fed the synbiotic mixture, the allergic skin response and the anaphylactic reaction were strongly reduced compared with whey-sensitized mice fed the control diet (P < 0.01). Immunofortis or B. breve M-16V alone were significantly less effective in reducing the allergic skin response than the synbiotic diet and did not reduce the anaphylactic reaction. The whey-specific IgE and IgG₁ responses were not affected; however, IgG₂a was greater in all treated groups than in the control group (P < 0.05). Serum mMCP-1 concentrations, reflecting mucosal mast cell degranulation, were lower in mice fed synbiotics compared with those fed the control diet (P < 0.01). Dietary supplementation with Immunofortis, B. breve M-16V, and particularly the synbiotic mixture, provided during sensitization, reduces the allergic effector response in a murine model of IgE-mediated hypersensitivity that mimics the human route of sensitization. This model shows the potential for dietary intervention with synbiotics in reducing the allergic response to food allergens.
Cow's milk-derived whey hydrolysates are nutritional substitutes for allergic infants. Safety or residual allergenicity assessment of these whey hydrolysates is crucial. Currently, rat basophilic ...leukemia RBL-2H3 cells expressing the human IgE receptor α-chain (huFcεRIα-RBL-2H3), sensitized with serum IgE from cow's milk allergic children, are being employed to assess in vitro residual allergenicity of these whey hydrolysates. However, limited availability and inter-lot variation of these allergic sera impede standardization of whey hydrolysate safety testing in degranulation assays.
An oligoclonal pool of chimeric human (chu)IgE antibodies against bovine β-lactoglobulin (a major allergen in whey) was generated to increase sensitivity, specificity, and reproducibility of existing degranulation assays.
Mice were immunized with bovine β-lactoglobulin, and subsequently the variable domains of dissimilar anti-β-lactoglobulin mouse IgG antibodies were cloned and sequenced. Six chimeric antibodies were generated comprising mouse variable domains and human constant IgE/κ domains.
After sensitization with this pool of anti-β-lactoglobulin chuIgEs, huFcεRIα-expressing RBL-2H3 cells demonstrated degranulation upon cross-linking with whey, native 18 kDa β-lactoglobulin, and 5-10 kDa whey hydrolysates, whereas a 3 kDa whey hydrolysate and cow's milk powder (mainly casein) showed no degranulation. In parallel, allergic serum IgEs were less sensitive. In addition, our pool anti-β-lactoglobulin chuIgEs recognized multiple allergenic immunodominant regions on β-lactoglobulin, which were also recognized by serum IgEs from cow's milk allergic children.
Usage of our 'unlimited' source and well-defined pool of β-lactoglobulin-specific recombinant chuIgEs to sensitize huFcεRIα on RBL-2H3 cells showed to be a relevant and sensitive alternative for serum IgEs from cow's milk allergic patients to assess safety of whey-based non-allergic hydrolyzed formula.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background. In previous studies, we showed that a fructo-oligosaccharide- (FOS-) supplemented diet enhanced oral immunotherapy (OIT) efficacy in a mouse model for cow’s milk allergy. Fermentation of ...FOS by intestinal bacteria leads to production of short-chain fatty acids (SCFA) including butyrate. Aim. To investigate the contribution of butyrate in the enhanced efficacy of OIT + FOS. Methods. C3H/HeOuJ mice were sensitized and received OIT with or without FOS or butyrate supplementation. After treatment, whole blood was collected to conduct a basophil activation test (BAT) and allergen challenges were performed to measure acute allergic symptoms. CD4 + CD25 + regulatory T cells (Tregs) were isolated from treated mice or differentiated in vitro and used in a bone marrow-derived mast cell (BMMC) suppression assay. Cecum content was collected to analyze SCFA concentrations. Results. Allergen-induced basophil activation was reduced in OIT + butyrate samples compared to OIT. Accordingly, the acute allergic skin response and mast cell degranulation upon challenge were reduced in OIT + butyrate and OIT + FOS mice compared to sensitized controls. Butyrate was increased in the cecum content of OIT + FOS mice compared to OIT mice and sensitized controls. Treg-mediated BMMC suppression was enhanced after in vivo butyrate and FOS exposure in combination with OIT but with a more pronounced effect for butyrate. Conclusion. Butyrate supplementation enhanced OIT-induced desensitization of basophils and mast cells and Treg functionality. Only OIT + FOS treatment induced potential microbial alterations, shown by increased butyrate levels in cecum content. Both butyrate and FOS are promising candidates to improve OIT efficacy in human studies to treat food allergies.
Dietary intervention with a unique prebiotic nondigestible carbohydrate mixture has been shown to reduce the development of allergic disease in infants at risk. In this study, the involvement of ...CD25⁺ regulatory T-cells (Treg) in the carbohydrate-induced effects was investigated in mice orally sensitized with whey using adoptive transfer experiments. Donor mice were sensitized with whey and fed a diet containing short-chain galacto-, long-chain fructo- and acidic-oligosaccharides, or a control diet starting 2 wk before sensitization. The acute allergic skin reaction upon intradermal whey challenge was determined and whey-specific Ig were measured. Splenocytes of the donor mice were transferred to naïve recipient mice after partial ex vivo depletion of CD25⁺ Treg. The prebiotic diet clearly diminished the acute allergic skin reaction (P < 0.001). Whey-sensitized recipient mice transferred with splenocytes from whey-sensitized, prebiotic-fed donor mice displayed almost complete prevention of the acute allergic skin reaction compared with mice receiving cells from sham-sensitized, prebiotic-fed donor mice (P < 0.001). Partial depletion of CD25⁺ T-cells inhibited these effects (P < 0.001), although IgE sensitization was not prevented. This study indicates the involvement of whey-specific CD25⁺ Treg in the suppression of the allergic effector response induced by dietary intervention with prebiotics.
Immunoglobulin E (IgE)-mediated allergy against cow's milk protein fractions such as whey is one of the most common food-related allergic disorders of early childhood. Histone acetylation is an ...important epigenetic mechanism, shown to be involved in the pathogenesis of allergies. However, its role in food allergy remains unknown. IgE-mediated cow's milk allergy was successfully induced in a mouse model, as demonstrated by acute allergic symptoms, whey-specific IgE in serum, and the activation of mast cells upon a challenge with whey protein. The elicited allergic response coincided with reduced percentages of regulatory T (Treg) and T helper 17 (Th17) cells, matching decreased levels of H3 and/or H4 histone acetylation at pivotal Treg and Th17 loci, an epigenetic status favoring lower gene expression. In addition, histone acetylation levels at the crucial T helper 1 (Th1) loci were decreased, most probably preceding the expected reduction in Th1 cells after inducing an allergic response. No changes were observed for T helper 2 cells. However, increased histone acetylation levels, promoting gene expression, were observed at the signal transducer and activator of transcription 6 (
) gene, a proallergic B cell locus, which was in line with the presence of whey-specific IgE. In conclusion, the observed histone acetylation changes are pathobiologically in line with the successful induction of cow's milk allergy, to which they might have also contributed mechanistically.
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