Mouse Model Of Food Allergy Research Articles

Suppressive effect of black tea polyphenol theaflavins in a mouse model of ovalbumin-induced food allergy.

Food allergy is recognized as a global medical problem with increasing prevalence in recent years. Currently, the treatment of food allergy mainly involves avoidance of allergens and allergen-specific immunotherapy. Barring the spontaneous resolution of food allergy during the growth process, this disease is difficult to treat fundamentally. In recent years, the use of functional food ingredients derived from natural products has been attracting attention for their prophylactic use in food allergy. Theaflavins, i.e., black tea polyphenols, are potent antioxidants that have inhibitory effects on a variety of diseases. However, little is known about the preventive effect of theaflavins on food allergy. In this study, we designed a mouse model of food allergy and examined the effect of theaflavins using the severity of diarrhea, a symptom of food allergy, as an indicator. The administration of a black tea extract rich in theaflavins or theaflavin 1 (subgroup of theaflavins) to mice reduced the severity of diarrhea when compared with a normal diet. A reduction in malondialdehyde levels, a key marker of lipid peroxidation, was also observed. Overall, these data suggest that theaflavins may potentially inhibit food allergy by alleviating oxidative stress in the colon and can be a potential food material for prevention of food allergy.

Front Cover: Effects of Allergen‐Specific and Non‐Specific AGEs on the Allergenicity of Ovalbumin in a Mouse Model of Food Allergy

Mol. Nutr. Food Res. 2023, 67, 202200221 DOI: 10.1002/mnfr.202200221 Epidemiologic evidence suggests a link between food allergy and the intake of advanced glycation end-products (AGEs). This study investigated the role of allergen-specific and non-specific AGEs in allergenicity of ovalbumin (OVA) in a mouse model of food allergy. The OVA-AGE elicits a stronger Th2-response than native OVA, in comparison to severer disruptions in gut barrier function and gut microbiota in mice exposed to non-relevant AGEs. This is reported by Shuifeng Zhang, Linglin Fu, and co-workers in article number 2200221.

Continuous ingestion of sodium chloride solution promotes allergen absorption and may exacerbate allergy symptoms on ovalbumin-induced food allergy in mice.

Various studies have reported relationships between salt intake and diseases, such as hypertension, cardiovascular disease, stroke, gastric cancer, and bronchial asthma. However, no reports exist on the relationship between salt intake and food allergies. In this study, we investigated the effect of continuous ingestion of sodium chloride (NaCl) on allergy symptoms using a mouse model of food allergy. BALB/c mice were divided into four groups of 6-8 animals each. The control-water group (CW) and sensitization-water group (SW) groups were provided free access to water, and the control-1% NaCl group (CS) and sensitization-1% NaCl group (SS) groups were provided a 1% NaCl solution. The SW and SS groups were sensitized with 50 µg ovalbumin (OVA) at 2 timepoints by intraperitoneal injection. After oral administration of OVA, anaphylactic response was measured and blood was collected. The mice were sacrificed, and serum levels of OVA and anti-OVA immunoglobulin (Ig)E and IgG1 were measured by enzyme-linked immunosorbent assays. The sodium ion (Na+) concentrations in duodenal and jejunal extracts were measured using a Na+ ion meter. The results suggested that continuous ingestion of a 1% NaCl solution for 36 days promoted allergen absorption and may have aggravated allergy symptoms in the mice. However, NaCl ingestion did not affect Na+ concentrations in the small intestine or OVA-specific antibody production.

Acute systemic myeloid inflammatory and stress response in severe food allergic reactions.

Food allergic reactions can be severe and potentially life-threatening and the underlying immunological processes that contribute to the severity of reactions are poorly understood. The aim of this study is to integrate bulk RNA-sequencing of human and mouse peripheral blood mononuclear cells during food allergic reactions and in vivo mouse models of food allergy to identify dysregulated immunological processes associated with severe food allergic reactions. Bulk transcriptomics of whole blood from human and mouse following food allergic reactions combined with integrative differential expressed gene bivariate and module eigengene network analyses to identify the whole blood transcriptome associated with food allergy severity. In vivo validation immune cell and gene expression in mice following IgE-mediated reaction. Bulk transcriptomics of whole blood from mice with different severity of food allergy identified gene ontology (GO) biological processes associated with innate and inflammatory immune responses, dysregulation of MAPK and NFkB signalling and identified 429 genes that correlated with reaction severity. Utilizing two independent human cohorts, we identified 335 genes that correlated with severity of peanut-induced food allergic reactions. Mapping mouse food allergy severity transcriptome onto the human transcriptome revealed 11 genes significantly dysregulated and correlated with severity. Analyses of whole blood from mice undergoing an IgE-mediated reaction revealed a rapid change in blood leukocytes particularly inflammatory monocytes (Ly6Chi Ly6G- ) and neutrophils that was associated with changes in CLEC4E, CD218A and GPR27 surface expression. Collectively, IgE-mediated food allergy severity is associated with a rapid innate inflammatory response associated with acute cellular stress processes and dysregulation of peripheral blood inflammatory myeloid cell frequencies.

Functional profiling of allergen-specific effector CD4+ T cells in mouse models of food allergy

Allergen-specific T cells have demonstrated to be crucial in the course of food allergy. We hypothesized that the identification of allergen-specific T cells by using activation markers may allow their monitoring at effector sites. The aim of this study is to identify the functional profile of allergen-specific T cells a murine model of food allergy.

The Intestinal Adipokine Resistin-like Molecule Beta Is Dysregulated In Children With Food Allergy

Food allergy (FA) is increasing, yet accurate biomarkers and disease-modifying treatments are still lacking, reflecting incomplete understanding of FA pathogenesis. In a mouse model of FA, Resistin-like molecule beta (RELMb) – a gut-derived cytokine involved in both allergic responses and protection from pathogens - is dysregulated, and its deletion results in protection from food-induced anaphylaxis.

Effects of Allergen-Specific and Non-Specific AGEs on the Allergenicity of Ovalbumin in a Mouse Model of Food Allergy.

Epidemiologic studies suggest a link between the incidence of food allergy and the consumption of dietary advanced glycation end-products (AGEs). However, the pathogenic role of dietary AGEs in food allergy is largely unknown. This study aims to investigate the effect of allergen-specific and non-specific AGEs on the allergenic manifestation of ovalbumin (OVA), a typical food allergen in vivo. OVA is glycated by methylglyoxal to prepare allergen-specific AGEs (i.e., OVA-AGE), and a standard AIN-93G diet is heated to obtain allergen-non-specific AGEs. A BALB/c mouse model orally sensitizes to OVA with different forms of AGEs is established and the outcomes are measured as clinical signs, specific antibodies, type-2/type-2 cytokines, immune cell subpopulations, intestinal barrier function, and gut microbiota (GM) composition. The OVA-AGE which has a lower immunoglobulin E (IgE)-binding level in vitro does not reduce the allergenicity of OVA but promotes a stronger T helper 2 cells (Th2)-response than native OVA in vivo. Both forms of AGEs up-regulate the expression of splenic RAGE and aggravate the destruction of gut barrier and GM dysbiosis, especially when exposes to non-relevant AGEs. This study highlights the role of dietary AGEs in food allergy and helps to understand the biological consequences of immune-toxic compounds in modern diet.

Oleuropein Prevents OVA-Induced Food Allergy in Mice by Enhancing the Intestinal Epithelial Barrier and Remodeling the Intestinal Flora.

This study assesses whether oleuropein prevents ovalbumin (OVA)-induced food allergy (FA) and investigates the underlying mechanisms. A Balb/c FA mouse model is established and maintained for 7 weeks. The subjects are administered OVA by oral gavage to induce FA and supplemented with different oleuropein doses (1.00-20.00mgkg-1 per day) to evaluate its preventative efficacy. The results indicate that oleuropein effectively alleviates OVA-induced allergy symptoms and promotes temperature elevation in sensitized mice. The secretion of serology-specific OVA-immunoglobulin (Ig)E, OVA-IgG, and histamine is inhibited in the sensitized mice. Oleuropein dramatically upregulates the expression of intestinal tight junction (TJ) proteins, regenerating gene (Reg) IIIγ, and interleukin (IL)-22, enhancing the physical and biochemical barrier function of the intestinal epithelium. Additionally, oleuropein improves the immune homeostasis of the intestinal epithelium by affecting the function of mucosal mast cells and regulatory T (Treg) cells. The disordered intestinal flora of the sensitized mice also improves after oleuropein administration. These findings suggest that oleuropein prevents FA by enhancing intestinal epithelial barrier function and improving immune homeostasis and intestinal flora in sensitized mice. Therefore, diets rich in oleuropein should be recommended for people with FA.

The environmental pollutant 3-methyl-4-nitrophenol reduces the regulatory T cells in the intestine

Dysfunction of immune regulation plays a crucial role in the pathogenesis of many immune disorders in the body. The underlying mechanism is still not completely understood. Environmental pollution contributes to immune de-regulation. 3-methyl-4-nitrophenol (MNP) is one of the major environmental pollutants. This study aims to investigate the role of MNP in compromising immune regulatory functions in the intestine. A food allergy (FA) mouse model was established using ovalbumin (OVA) as the specific antigen. The activities of regulatory T cells in the mouse intestine were evaluated by flow cytometry and enzyme-linked immunosorbent assay. We found that MNP reduced the CD4+ Foxp3+ Treg frequency, increased Th17 cells, and converted Tregs to Th17 cells in the intestine. MNP induced the expression of IL-6 in regulatory T cells (Tregs). Estrogen receptor (ER) mediated the effects of MNP on promoting IL-6 expression in Tregs. The IL-6 in synergy with transforming growth factor (TGF)-β to convert Tregs to Th17 cells. The concomitant exposure of MNP and OVA induced FA like response in mice. Modulation of the ER-STAT3-IL-6 signal pathway attenuated mouse FA response. In summary, MNP, an environmental pollutant, acts as an immunoadjuvant for developing FA. By activation of the estrogen receptor, MNP induces Tregs to express IL-6. IL-6 in synergy with TGF-β converts Tregs to Th17 cells.

Suitability of potyviral recombinant virus-like particles bearing a complete food allergen for immunotherapy vaccines.

Virus-like particles (VLPs) have been gaining attention as potential platforms for delivery of cargos in nanomedicine. Although animal viruses are largely selected due to their immunostimulatory capacities, VLPs from plant viruses constitute a promising alternative to be considered. VLPs derived from Turnip mosaic virus (TuMV) have proven to present a tridimensional structure suited to display molecules of interest on their surface, making them interesting tools to be studied in theragnostic strategies. Here, we study their potential in the treatment of food allergy by genetically coupling TuMV-derived VLPs to Pru p 3, one of the most dominant allergens in Mediterranean climates. VLPs-Pru p 3 were generated by cloning a synthetic gene encoding the TuMV coat protein and Pru p 3, separated by a linker, into a transient high-expression vector, followed by agroinfiltration in Nicotiana benthamiana plants. The generated fusion protein self-assembled in planta to form the VLPs, which were purified by exclusion chromatography. Their elongated morphology was confirmed by electron microscopy and their size (~400 nm), and monodispersity was confirmed by dynamic light scattering. Initial in vitro characterization confirmed that they were able to induce proliferation of human immune cells. This proliferative capability was enhanced when coupled with the natural lipid ligand of Pru p 3. The resultant formulation, called VLP-Complex, was also able to be transported by intestinal epithelial cells, without affecting the monolayer integrity. In light of all these results, VLP-Complex was furtherly tested in a mouse model of food allergy. Sublingual administration of VLP-Complex could effectively reduce some serological markers associated with allergic responses in mice, such as anti-Pru p 3 sIgE and sIgG2a. Noteworthy, no associated macroscopic, nephritic, or hepatic toxicity was detected, as assessed by weight, blood urea nitrogen (BUN) and galectin-3 analyses, respectively. Our results highlight the standardized production of allergen-coated TuMV-VLPs in N. benthamiana plants. The resulting formula exerts notable immunomodulatory properties without the need for potentially hazardous adjuvants. Accordingly, no detectable toxicity associated to their administration was detected. As a result, we propose them as good candidates to be furtherly studied in the treatment of immune-based pathologies.

Asymptomatic sensitization to a cow's milk protein induces sustained neuroinflammation and behavioral changes with chronic allergen exposure.

Mouse models of food allergy have contributed to our understanding of various aspects of the disease, including susceptibilities, symptom spectra, cellular mechanisms, and therapeutic approaches. Previously, we used a mouse model of non-anaphylactic cow’s milk allergy (CMA) and investigated sex- and strain-dependent differences in immunological, neurological, and behavioral sequelae. We showed that male C57BL/6J mice sensitized to a bovine whey protein, β-lactoglobulin (BLG; Bos d 5), exhibited anxiety- and depression-like behavior upon acute allergen challenge. Systemic levels of BLG-specific immunoglobulins, cytokines and chemokines were also elevated in the sensitized mice. Furthermore, neuroinflammation and intestinal dysbiosis were evident as the possible causes of the altered behavior. To assess whether frequent allergen exposure influences CMA-associated pathologies over an extended period in this subclinical model, we placed BLG-sensitized mice on a whey protein (WP)-containing or whey-free control (CTL) diet for 3 months. As expected, allergen-specific IgE was significantly elevated in the plasma after completing the 5-week sensitization phase. However, the IgE levels declined in both diet groups after 3 months. In contrast, allergen-specific IgG1 stayed elevated in sensitized mice with the CTL diet, and the WP diet to a lesser extent. Interestingly, BLG-sensitized mice on the WP diet exhibited anxiety-like behavior and a trend toward spatial memory decline compared to the sham or the sensitized mice on the CTL diet. Moreover, increased immunoreactivities for GFAP and Iba1 and elevated levels of CXCL13 and CCL12, the chemokines involved in central leukocyte recruitment and other neurological diseases, were also observed in the brain. We demonstrated that sensitization to the whey protein, particularly with continuous allergen exposure, resulted in persistent neuroinflammation and associated behavioral changes despite lowered allergen-specific immunoglobulin levels. These results suggested that continuous consumption of the offending allergen may lead to adverse consequences in the brain even after desensitization.

Semaphorin-3 Promotes Specific Immunotherapy Effects on Experimental Food Allergy.

Sustaining higher frequency of mast cells in the allergic lesion site has been recognized. Factors causing high numbers of mast cells in the local tissues are not fully understood yet. RAS signaling plays a role in sustaining certain cell activities. This study is aimed at elucidating the role of RAS activation in the apoptosis resistance induction in mast cells and at employing semaphorin 3A to regulate RAS activities in sensitized mast cells and alleviating the allergic response in the intestine. A food allergy (FA) mouse model was developed. Mast cells were isolated from FA mouse intestinal tissues by flow cytometry. Mast cell apoptosis was assessed by staining with annexin V and propidium iodide. We found that aberrantly higher p21-activated kinase-1 (Pak1) expression in FA mast cells was associated with mast cell aggregation in the intestine. Sensitization increased Pak1 expression and apoptosis resistance in intestinal mast cells. RAS and Pak1 mutually potentiated each other in sensitized mast cells. Semaphorin 3A (sema3A) suppressed the Pak1 expression and RAS activation in mast cells. sema3A restored the apoptosis sensitivity in sensitized mast cells. Administration of sema3A potentiated allergen-specific immunotherapy in experimental FA. In conclusion, mast cells of FA mice showed higher Pak1 expression and high RAS activation status that contributed to apoptosis resistance in mast cells. Administration of sema3A restored the sensitivity to apoptosis inducers and promoted the therapeutic effects of specific immunotherapy on experimental FA.

Oral exposure to bisphenol A exacerbates allergic inflammation in a mouse model of food allergy

Allergic diseases are increasing worldwide, and their precise causes are not fully understood. However, this observation can be correlated with growing chemical pollution of the environment. Bisphenol A (BPA) alters the immune system, microbiota and barrier functions. Here, we studied the effect of oral BPA at levels equivalent to human exposure to understand the mechanisms of immunological, physiological and microbial action on food allergies. In a murine model of allergy, we evaluated the effect of direct oral exposure to BPA at 4 µg/kg bw/d corresponding to tolerable daily intake (TDI). We studied symptoms, intestinal physiology and humorall and cellular immune responses during food allergy. We explored the relationship between oral exposure to BPA and changes in the gut microenvironment. Markers of food allergy and intestinal permeability were increased following exposure to BPA. We also observed a modulated humorall and T-cell response with aggravation of food allergy inflammation. Moreover, BPA exposure induced gut dysbiosis and decreased microbial diversity induced by food allergy. Altogether, these results suggest that the 2015 European Food Safety Authority (EFSA) TDI should be reviewed to consider the immunotoxicity of BPA.

House dust mite exposure enhances immune responses to ovalbumin-induced intestinal allergy

House dust mites (HDM) are one of the important factors of airway allergic diseases, HDM allergens can be detected in the human gut mucosa, which induces local inflammation and increases intestinal epithelial permeability. This study tests a hypothesis that HDM contribute to the development of OVA (ovalbumin)-induced intestinal allergy. The serum levels of IgE against HDM in patients with food allergy were detected with UniCAP100 (Pharmacia, Uppsala, Sweden); a mouse model of food allergy was developed with OVA and HDM as the specific antigens. Compared to healthy controls, patients with food allergy have higher levels of serum HDM-specific IgE. Compared to food allergy alone groups, the levels of HDM-specific IgE in patients with food allergy and asthma or allergic rhinitis were significantly higher. In mouse models, we found that HDM/OVA induced allergy-like symptoms, lower body temperature, and lower body weight. The levels of IgE, IgG1, mMCP-1 (mouse mast cell protease-1), IL-4 and IL-5 in the HDM and HDM + CT (cholera toxin) groups were higher than the control groups, and the levels of IgE, IgG1, IL-4 and IL-5 in the HDM, OVA and HDM + OVA groups were higher than the control groups. The pathological changes of intestinal tissues in the HDM and HDM + CT/the HDM, OVA and HDM + OVA groups were more severe, more eosinophil infiltration than the control groups. Moreover, exposure to HDM induced intestinal barrier dysfunction, and facilitated the development of intestinal allergy in mice. In conclusion, HDM exposure enhances immune responses to OVA-induced food allergy.

Mouse Models of Food Allergy in the Pursuit of Novel Treatment Modalities.

The prevalence of IgE-mediated food allergies has increased dramatically in the past three decades, now affecting up to 10% of the US population. IgE-mediated food allergy is an immunologic disease, involving a variety of cells, including B and T cells, mast cells, basophils, ILC2s, and epithelial cells. Mouse models of food allergy mimic the overall immunologic processes known to exist in humans. Due to the limitations of invasive sampling of human tissue and the similarities of the human and mouse immune systems, comprehensive pathogenesis studies of food allergy have been performed in mouse models. Mouse models have been effective in elucidating the roles of non-oral routes of sensitization and identifying key cells and molecules involved in allergic sensitization. Furthermore, the development of novel therapeutic approaches for food allergy has been accelerated through the use of pre-clinical mouse models. Despite the groundbreaking findings stemming from research in mice, there are continued efforts to improve the translational utility of these models. Here, we highlight the achievements in understanding food allergy development and efforts to bring novel treatment approaches into clinical trials.

A High-Sodium Diet Modulates the Immune Response of Food Allergy in a Murine Model.

Mounting evidence demonstrates that a high-salt diet (HSD) not only affects hemodynamic changes but also disrupts immune homeostasis. The T helper 17 (Th17) and regulatory T cells (Tregs) are susceptible to hypersalinity. However, research on the influence of sodium on Th2-mediated food allergies remains scarce. We aimed to investigate the effect of dietary sodium on the immune response to food allergies. Mice maintained on an HSD (4% NaCl), low-salt diet (LSD; 0.4% NaCl), or control diet (CTRL; 1.0% NaCl) were orally sensitized with ovalbumin (OVA) and a cholera toxin (CT) adjuvant, and then subjected to an intragastric OVA challenge. OVA-specific immunoglobulin G (IgG), IgG1, IgG2a, and IgE antibodies were significantly higher in the HSD group than in the CTRL group (p < 0.001, p < 0.05, p < 0.01, and p < 0.05, respectively). Mice on HSD had significantly higher interleukin (IL)-4 levels than the CTRL group (p < 0.01). The IL-10 levels were significantly lower in the HSD group than in the CTRL group (p < 0.05). The serum levels of interferon-γ (IFN-γ), sodium, and chloride did not differ among the three groups. This study indicates that excessive salt intake promotes Th2 responses in a mouse model of food allergy.

Reduction of allergy effects of peanut sprout extract in a systemic anaphylaxis food allergy mouse model

Reduction of allergy effects of peanut sprout extract in a systemic anaphylaxis food allergy mouse model

The role of the stress-activated transcription factor Nrf2 in OVA-induced food allergy

Abstract Food allergies are rising at a striking rate, but the underlying cause is unclear. The purpose of the studies was to determine the effect of the food preservative tert-butylhydroquinone (tBHQ) in a mouse model of food allergy. Our preliminary studies show that skin-sensitization with OVA induced an elevated OVA-IgE level in mice on a tBHQ diet. Likewise, in response to oral challenge, a greater decrease in body temperature during anaphylaxis was observed in the tBHQ group. Previously published in vitro studies suggest that tBHQ promotes Th2 polarization through activation of the stress-activated transcription factor, Nrf2. Therefore, we proposed the hypothesis that tBHQ exacerbates allergic response in OVA sensitized mice through activation of Nrf2. We implemented adoptive transfers of CD4 T cells from wild-type or Nrf2-null mice into immunodeficient mice (all mice received wild-type B cells). The study revealed marked genotype differences. Notably, dietary tBHQ had little effect on food allergy in recipients of Nrf2-deficient CD4 T cells. These mice showed attenuated sensitization as compared to wild-type CD4 T cells recipients. Strikingly, mice receiving Nrf2-deficient T cells did not become anaphylactic following challenge. In contrast, tBHQ caused an increase in OVA-IgE levels and a greater drop in body temperature in mice receiving wild-type CD4 T cells, suggesting these effects are Nrf2 dependent. In addition, recipients of Nrf2-deficient CD4 T cells showed an attenuated percentage of Th2 cells and mast cell degranulation response, following challenge. Taken together, these data suggest a critical role for Nrf2 during food allergy and demonstrate that tBHQ exacerbates food allergy in a CD4 T cell-Nrf2 dependent manner.

The role of the stress‐activated transcription factor Nrf2 in OVA‐induced food allergy

Immune-mediated adverse reactions to food allergens are rising at a striking rate, but the underlying cause is unknown. The purpose of the present studies was to determine the effect of the food preservative tert-butylhydroquinone (tBHQ) on anaphylaxis in a mouse model of food allergy. Our preliminary studies demonstrate that skin-sensitization with OVA induced a markedly higher OVA-specific IgE response in mice on a tBHQ diet. Likewise, in response to OVA challenge by the oral route, a greater decrease in body temperature during anaphylaxis was observed in the tBHQ-treated group. Previously published in vitro studies suggest that tBHQ promotes Th2 polarization, a key step in the development of allergy, through activation of the stress-activated transcription factor, Nrf2. Therefore, we proposed the hypothesis that tBHQ exacerbates allergic response in ovalbumin (OVA) sensitized mice through activation of Nrf2. We implemented adoptive transfers of CD4 T cells from wild-type or Nrf2-null mice into immunodeficient SCID mice (all mice also received wild-type B cells). The study revealed marked genotype differences. Notably, dietary tBHQ had little effect on food allergy in recipients of Nrf2-deficient CD4 T cells. These mice showed markedly attenuated sensitization as compared to mice who received wild-type CD4 T cells. Strikingly, mice receiving Nrf2-deficient T cells did not become anaphylactic following OVA challenge. In contrast, tBHQ caused an increase in OVA-IgE plasma levels and a greater drop in body temperature in mice receiving wild-type CD4 T cells, suggesting these effects are Nrf2 dependent. In addition, recipients of Nrf2-deficient CD4 T cells showed a greatly attenuated percentage of Th2 cells and mucosal mast cell degranulation response, following OVA challenge. Taken together, these data suggest a critical role for Nrf2 during food allergen-induced sensitization and anaphylaxis and demonstrate that tBHQ exacerbates food allergy in a CD4 T cell- Nrf2 dependent manner in mice.

Modulating oxidative stress counteracts specific antigen-induced regulatory T-cell apoptosis in mice.

Treg are known to have a central role in orchestrating immune responses, but less is known about the destiny of Treg after being activated by specific Ags. This study aimed to investigate the role of superoxide dismutase, an active molecule in the regulation of oxidative stress in the body, in the prevention of Treg apoptosis induced by specific Ags. Ag-specific Tregs were isolated from the DO11.10 mouse intestine. A food allergy mouse model was developed with ovalbumin as the specific Ag and here, we observed that exposure to specific Ag induced Treg apoptosis through converting the precursor of TGF-β to its mature form inside the Tregs. Oxidative stress was induced in Tregs upon exposure to specific Ags, in which Smad3 bound the latency-associated peptide to induce its degradation, converting the TGF-β precursor to its mature form, TGF-β. Suppressing oxidative stress in Tregs alleviated the specific Ag-induced Treg apoptosis in in vitro experiments and suppressed experimental food allergy by preventing the specific Ag-induced Treg apoptosis in the intestine. In conclusion, exposure to specific Ags induces Treg apoptosis and it can be prevented by upregulating superoxide dismutase or suppressing reactive oxidative species in Tregs.