Mouse Model Of Food Allergy Research Articles

Sea Buckthorn Flavonoid Extracted with High Hydrostatic Pressure Alleviated Shrimp Allergy in Mice through the Microbiota and Metabolism.

Sea buckthorn (Hippophaë rhamnoides L.) known as the deciduous shrub has been reported to have effects of antioxidant, anti-inflammatory, and immunomodulatory activities. Tropomyosin (TM) induced a regulatory immune response associated with food allergy. In this study, a mouse model of food allergy sensitized to tropomyosin (TM) was established to assess the antiallergic properties of sea buckthorn flavonoid extract (SBF). SBF alleviated mice's allergic symptoms and exhibited a significant reduction in the levels of IgE and histamine. Meanwhile, SBF repaired the allergic Th2 cell overpolarization generated by TM, via downregulating the IL-4 production and upregulating IFN-γ production to restore the balance of Th1/Th2 cells. Furthermore, the 16S RNA analysis showed that SBF primarily restored the gut microbiota via increasing the abundance in Chitinophilidae and decreasing in Burkholderiaceae, Pneumatobacteriaceae, and Sphingomonadaceae. Gut metabolomes determined by liquid chromatography-mass spectrometry (LC-MS) suggested that TM upregulated PE (14:0/22:1(13Z)) and SBF decreased formimino-l-glutamic acid and urocanic acid levels. According to the KEGG pathway analysis, SBF treatment has been shown to modulate glycerophospholipid and histidine metabolism to improve allergic reactions. SBF holds great promise as a novel potential agent for the treatment of food allergies.

The Immune Regulatory Functions in B Cells Are Restored by CpG to Reduce Experimental Food Allergy.

Dysfunctional immune regulation contributes to the pathogenesis of food allergy (FA). The mechanism behind regulatory B-cell dysfunction is unclear. CpG has immune regulatory functions. The purpose of this study is to use CpG to recover the immune suppressive functions of B cells in mice with FA. An FA mouse model was created using ovalbumin as the specific antigen. Flow cytometry was used to isolate B cells from the intestinal tissues. The immune regulatory functions of B cells were assessed using immunological approaches. The results showed that the FA response was linked to low IL-10 levels in gut lavage fluids of FA mice. FA mouse intestinal B cells produced lower amounts of IL-10 as compared with B cells isolated from naïve control mice. Impaired immune suppressive functions were observed in B cells isolated from the FA mouse intestine. The inducibility of the Il10 expression in naïve B cells of the intestine of FA mice was defective. The induction of Il10 expression in FA B cells could be restored by CpG through regulating the methylation status of the Cmip promoter. CpG promoted the therapeutic efficacy of allergen specific immunotherapy by restoring the induction of IL-10+ B cells in the intestine. The expression of Il10 in B cells of the FA mouse intestine was impaired. Administration of CpG could restore the expression of Il10 in B cells in the intestine and promote immunotherapy for FA.

Ovalbumin-induced food allergy suppression via regulatory T cell expansion mediated by a TNFR2 agonist in mice

Food allergies represent a growing health concern worldwide, characterized by abnormal immune responses to specific dietary antigens. This condition is often associated with a dysregulation of immune tolerance, especially within the intestinal mucosa. Regulatory T cells (Tregs), a crucial subset of lymphocytes, play a central role in maintaining peripheral immune tolerance and are abundant in the intestinal lamina propria. Recent studies have highlighted Treg dysfunction in patients with food allergies, suggesting a potential connection between impaired Treg function and allergy onset. Therefore, strategies to adequately control and activate Tregs could offer new avenues for the prevention and treatment of food allergies. Our research focuses on targeting the regulatory molecule, tumor necrosis factor receptor type 2 (TNFR2), a key modulator of Treg function. We have developed a TNFR2 agonist, scR2agoTNF-Fc, characterized by high TNFR2-stimulating activity and enhanced blood retention in vivo for Treg expansion. In this study, we utilized an ovalbumin (OVA)-induced food allergy mouse model to verify the therapeutic potential of scR2agoTNF-Fc in modulating allergic responses and restoring immune balance. The results showed that scR2agoTNF-Fc promoted the expansion of Treg population in vivo in mice. In addition, scR2agoTNF-Fc reduced diarrhea caused by the food allergy. This was consistent with the molecular mechanisms of suppression of blood immunoglobulins and Th2 cells. Therefore, it was shown that quantitative and functional enhancement of Tregs by the TNFR2 agonist, scR2agoTNF-Fc, may be effective in treating food allergies.

Phosphoryl oligosaccharide alleviates food allergy by suppressing IgE class switch recombination through LCN2 pathway

Specific algal polysaccharides exhibit significant anti-allergic activity. B cell class switch recombination (CSR) is a crucial step in food allergies, however, the role of polysaccharides in regulating CSR remains unclear. To investigate the regulation of B cell CSR by algal polysaccharides, an in vitro IgE-type CSR cell model was used to screen for active algal polysaccharides, and four active polysaccharides were identified. In a food allergy mouse model, Undaria pinnatifida polysaccharides (UPP) and phosphoryl oligosaccharides (POS) suppressed allergic responses and reduced the proliferation of IgE+ B cells. Transcriptome sequencing of B cells identified LCN2 as a potential target of POS, and inhibition of LCN2 blocked the activity of POS on CSR. These findings demonstrated the efficacy of POS in regulating B cell CSR and alleviating allergic responses and revealed the underlying mechanisms. This work provided data and theoretical support for the development of polysaccharide-based functional foods for individuals with allergies.

Inhibition of DNMT1 attenuates experimental food allergy

BackgroundThe treatment of food allergy (FA) needs improvement. The treatment of immune disorders can be improved by regulating epigenetic marks, which is a promising method. The objective of this research is to alleviate experimental FA by employing an inhibitor of DNA methyltransferase-1 (DNMT1). MethodsOvalbumin was used as the specific antigen to establish a mouse model of FA. Intestinal IL-35+ regulatory B cells (Breg cells) were isolated from FA mice, and characterized using immunological approaches. ResultsFA mice had a lower frequency of IL-35+ Breg cells, which was inversely correlated with their FA response. The quantity of IL-35 was lower in intestinal Breg cells from FA mice. Hypermethylation status was detected in the Il35 promoter, which was accompanied with high levels of H3K9me3. Enforced expression of DNMT1 hindered the promoter activity of the IL35 gene. Administration of an inhibitor of DNMT1 (RG108) restored the immune regulatory capacity of FA intestinal Bregs, and effectively suppressed the expression of DNMT1, and attenuated experimental FA. ConclusionsThe elevated quantity of DNMT1 in intestinal Breg cells compromises the expression of IL-35 and affects the immune regulatory functions, which facilitates the development of FA. The immune regulatory functions of intestinal Breg cells are restored and experimental FA is attenuated by inhibiting DNMT1.

Allergen-Encapsulating Nanoparticles Reprogram Pathogenic Allergen-Specific Th2 Cells to Suppress Food Allergy.

Food allergy is a prevalent, potentially deadly disease caused by inadvertent sensitization to benign food antigens. Pathogenic Th2 cells are a major driver for disease, and allergen-specific immunotherapies (AIT) aim to increase the allergen threshold required to elicit severe allergic symptoms. However, the majority of AIT approaches require lengthy treatments and convey transient disease suppression, likely due to insufficient targeting of pathogenic Th2 responses. Here, the ability of allergen-encapsulating nanoparticles to directly suppress pathogenic Th2 responses and reactivity is investigated in a mouse model of food allergy. NPs associate with pro-tolerogenic antigen presenting cells, provoking accumulation of antigen-specific, functionally suppressive regulatory T cells in the small intestine lamina propria. Two intravenous doses of allergen encapsulated in poly(lactide-co-glycolide) nanoparticles (NPs) significantly reduces oral food challenge (OFC)-induced anaphylaxis. Importantly, NP treatment alters the fates of pathogenic allergen-specific Th2 cells, reprogramming these cells toward CD25+FoxP3+ regulatory and CD73+FR4+ anergic phenotypes. NP-mediated reductions in the frequency of effector cells in the gut and mast cell degranulation following OFC are also demonstrated. These studies reveal mechanisms by which an allergen-encapsulating NP therapy and, more broadly, allergen-specific immunotherapies, can rapidly attenuate allergic responses by targeting pathogenic Th2 cells.

Oral administration of Bacillus coagulans TQ-35 alleviates allergic responses in OVA-sensitive BALB/c mice

Bacillus coagulans has been extensively studied so far, but there has been a lack of research on its usage in allergy. In this study, we designed to assess the effect of different concentrations of B. coagulans on food allergy in a BALB/c mouse model of ovalbumin (OVA)-induced food allergy and its effect on gut microbes. The assessment of symptoms, specific immunoglobulin E (IgE), T-cell differentiation, and related gene expression levels in sensitized mice by assay indicated that high doses of oral B. coagulans could alleviate allergic symptoms. Treatment with B. coagulans, in the high-dose group, significantly reduced IgE and IgG1 levels and modulated the balance of T helper type 1 cell (Th1) and Th2 and the expression of relevant genes in the spleen. 16S rRNA analysis showed that probiotics improved the structure of the microbiota, in particular by boosting the percentage of Clostridia, Bacteroides vulgatus and Enterococcus faecium, and by increasing the abundance of microbial species, thereby modulating the immune system. Therefore, this study can provide insights into the practical application of B. coagulans doses to alleviate OVA allergy.

Notch Signaling Inhibition Alleviates Allergies Caused by Antarctic Krill Tropomyosin through Improving Th1/Th2 Imbalance and Modulating Gut Microbiota.

Antarctic krill tropomyosin (AkTM) has been shown in mice to cause IgE-mediated food allergy. The objective of this work was to investigate the role of Notch signaling in AkTM-sensitized mice, as well as to determine the changes in gut microbiota composition and short-chain fatty acids (SCFAs) in the allergic mice. An AkTM-induced food allergy mouse model was built and N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) was used as an γ-secretase inhibitor to inhibit the activation of Notch signaling. Food allergy indices, some key transcription factors, histologic alterations in the small intestine, and changes in gut microbiota composition were examined. The results showed that DAPT inhibited Notch signaling, which reduced AkTM-specific IgE, suppressed mast cell degranulation, decreased IL-4 but increased IFN-γ production, and alleviated allergic symptoms. Quantitative real-time PCR and Western blotting analyses revealed that expressions of Hes-1, Gata3, and IL-4 were down-regulated after DAPT treatment, accompanied by increases in T-bet and IFN-γ, indicating that Notch signaling was active in AkTM-sensitized mice and blocking it could reverse the Th1/Th2 imbalance. Expressions of key transcription factors revealed that Notch signaling could promote Th2 cell differentiation in sensitized mice. Furthermore, 16S rRNA sequencing results revealed that AkTM could alter the diversity and composition of gut microbiota in mice, leading to increases in inflammation-inducing bacteria such as Enterococcus and Escherichia-Shigella. Correlation analysis indicated that reduced SCFA concentrations in AkTM-allergic mice may be related to decreases in certain SCFA-producing bacteria, such as Clostridia_UCG-014. The changes in gut microbiota and SCFAs could be partially restored by DAPT treatment. Our findings showed that inhibiting Notch signaling could alleviate AkTM-induced food allergy by correcting Th1/Th2 imbalance and modulating the gut microbiota.

Comparative analysis of tropomyosin allergenicity in three different species of molluscs: insights into the role of amino acid composition in IgE epitopes.

Limited research has been conducted on the differences in allergenicity among Alectryonella plicatula tropomyosin (ATM), Haliotis discus hannai tropomyosin (HTM), and Mimachlamys nobilis tropomyosin (MTM) in molluscs. Our study aimed to comprehensively analyze and compare their immunoreactivity, sensitization, and allergenicity while simultaneously elucidating the underlying molecular mechanisms involved. We assessed the immune binding activity of TM utilizing 86 sera from allergic patients and evaluated sensitization and allergenicity through two different types of mouse models. The dot-blot and basophil activation test assays revealed strong immunoreactivity for HTM, ATM, and MTM, with HTM exhibiting significantly lower levels compared to ATM. In the BALB/c mouse sensitization model, all TM groups stimulated the production of specific antibodies, elicited IgE-mediated immediate hypersensitivity responses, and caused an imbalance in the IL-4/IFN-γ ratio. Similarly, in the BALB/c mouse model of food allergy, all TM variants induced IgE-mediated type I hypersensitivity responses, leading to the development of food allergies characterized by clinical symptoms and an imbalance in the IL-4/IFN-γ ratio. The stimulation ability of sensitization and the severity of food allergies consistently ranked as ATM > MTM > HTM. Through an in-depth analysis of non-polar amino acid frequency and polar hydrogen bonds, HTM exhibited higher frequencies of non-polar amino acids in its amino acid sequence and IgE epitopes, in comparison with ATM and MTM. Furthermore, HTM demonstrated a lower number of polar hydrogen bonds in IgE epitopes. Overall, HTM exhibited the lowest allergenic potential in both allergic patients and mouse models, likely due to its lower polarity in the amino acid sequence and IgE epitopes.

In vivo evaluations of Lactobacillus-fermented Eucheuma spinosum polysaccharides on alleviating food allergy activity.

In order to explore the in vivo anti-food allergy activity of Lactobacillus sakei subsp. sakei-fermented Eucheuma spinosum polysaccharides F1-ESP-3, an ovalbumin (OVA)-induced food allergy mouse model was established by ascites immunization and gavage. The weight, temperature, incidence of diarrhea, levels of allergic mediators and inflammatory factors in the serum of mice were analyzed. We analyzed the differentiation of mouse spleen lymphocytes and the proportion of sensitized mast cells by flow cytometry. The intestinal barrier status of mice was analyzed by intestinal pathological tissue sections and microbiota sequencing. The results showed that F1-ESP-3 could alleviate the food allergy symptoms of mice, such as hypothermia and loose stool; levels of OVA-specific immunoglobulin E, mast cell protease and histamine in the serum of sensitized mice and the proportion of dendritic cells and mast cells in mouse spleen were significantly reduced; in addition, F1-ESP-3 may protect the intestinal barrier and further improve the intestinal microenvironment of food-allergic mice by regulating the abundance of Bacteroidetes and Firmicutes. F1-ESP-3 can further improve the intestinal microenvironment of food-allergic mice by upregulating the levels of Lachnospiraceae, and may affect the signal pathways such as NOD-like receptor, MAPK, I kappa B and antigen processing and presentation.

High intestinal isoleucine is a potential risk factor for food allergy by regulating the mTOR/AKT pathway in dendritic cells

Food allergy is a global food safety problem with a growing prevalence. People in industrial regions are more susceptible to allergy, but the mechanisms behind this are not fully understood. In this study, the probiotic Lactobacillus casei Zhang (LcZ) was administered to allergic individuals and the impact on allergy-related factors were determined. LcZ alleviated allergenic responses, and there was a significant correlation between the intestinal isoleucine content and IgE concentration. Metagenomics results suggest that the metabolism of the gut microbiota is a source of isoleucine. In a mouse model of food allergy, a high isoleucine diet exacerbated allergic responses and increased the activity of allergenic dendritic cell. In a dendritic cell model, a protein array revealed that the mTOR/AKT pathway mediated the function of isoleucine, and molecular docking suggested that Sestrin2 could be the potential receptor. Overall, this study revealed the role of isoleucine in promoting food allergy, elucidated the underlying mechanisms, and suggested that a high intake of isoleucine could be a potential risk factor for food allergy.

Comparison of immune responses and intestinal flora in epicutaneously sensitized BALB/c or C57BL/6 mouse models of food allergy

Cutaneous exposure to food allergens through a disrupted skin barrier is recognized as an important cause of food allergy, and the cutaneous sensitized mouse model has been established to investigate relevant allergic disorders. However, the role of different genetic backgrounds of mice on immune responses to food allergens upon epicutaneous sensitization is largely unknown. In this study, two strains of mice, i.e., the BALB/c and C57BL/6 mice, were epicutaneously sensitized with ovalbumin on atopic dermatitis (AD)-like skin lesions, followed by intragastric challenge to induce IgE-mediated food allergy. Allergic outcomes were measured as clinical signs, specific antibodies and cytokines, and immune cell subpopulations, as well as changes in intestinal barrier function and gut microbiota. Results showed that both strains of mice exhibited typical food-allergic symptoms with a Th2-skewed response. The C57BL/6 mice, rather than the BALB/c mice, were fitter for establishing an epicutaneously sensitized model of food allergy since a stronger Th2-biased response and severer disruptions in the intestinal barrier and gut homeostasis were observed. This study provides knowledge for selecting an appropriate mouse model to study food-allergic responses associated with AD-like skin lesions and highlights the role of genetic variations in the immune mechanism underlying pathogenesis of food allergy.

Animal Models in the Study of Food Allergens: Long-Term Maintenance of Allergic Reactivity in Mouse Models of Food Allergy.

Multiple mouse models have been used to characterize mechanisms of allergic sensitization and anaphylaxis and are widely used for preclinical development of novel therapeutics. However, the majority of published works with mouse models of food allergy have very short intervals between the time of sensitization and the end of the study, and the duration of maintenance of reactivity has not been widely reported. This chapter focuses on two of the most commonly used mouse models with sensitization to peanut or ovalbumin, with the focus on the long-term durability of sensitization to allow for longer therapeutic protocols and assessment of sustained unresponsiveness.

Combined oral intake of short and long fructans alters the gut microbiota in food allergy model mice and contributes to food allergy prevention

BackgroundIt has become clear that the intestinal microbiota plays a role in food allergies. The objective of this study was to assess the food allergy-preventive effects of combined intake of a short fructan (1-kestose [Kes]) and a long fructan (inulin ([Inu]) in an ovalbumin (OVA)-induced food allergy mouse model.ResultsOral administration of fructans lowered the allergenic symptom score and alleviated the decreases in rectal temperature and total IgA levels and increases in OVA-specific IgE and IgA levels induced by high-dose OVA challenge, and in particular, combined intake of Kes and Inu significantly suppressed the changes in all these parameters. The expression of the pro-inflammatory cytokine IL-4, which was increased in the allergy model group, was significantly suppressed by fructan administration, and the expression of the anti-inflammatory cytokine IL-10 was significantly increased upon Kes administration. 16 S rRNA amplicon sequencing of the gut microbiota and beta diversity analysis revealed that fructan administration may induce gut microbiota resistance to food allergy sensitization, rather than returning the gut microbiota to a non-sensitized state. The relative abundances of the genera Parabacteroides B 862,066 and Alloprevotella, which were significantly reduced by food allergy sensitization, were restored by fructan administration. In Parabacteroides, the relative abundances of Parabacteroides distasonis, Parabacteroides goldsteinii, and their fructan-degrading glycoside hydrolase family 32 gene copy numbers were increased upon Kes or Inu administration. The concentrations of short-chain fatty acids (acetate and propionate) and lactate were increased by fructan administration, especially significantly in the Kes + Inu, Kes, and Inu-fed (Inu, Kes + Inu) groups.ConclusionCombined intake of Kes and Inu suppressed allergy scores more effectively than single intake, suggesting that Kes and Inu have different allergy-preventive mechanisms. This indicates that the combined intake of these short and long fructans may have an allergy-preventive benefit.

Leuconostoc mesenteroides WHH1141 ameliorates ovalbumin-induced food allergy in mice.

Food allergy (FA) is acknowledged as a significant public health and food safety issue, due to its manifestation as an amplified immune reaction to food antigens. Recently, probiotics within Lactobacillus and Bifidobacterium have been highlighted as a promising strategy against allergic disease by modulating the balance of Th1/Th2 responses. However, the allergy-alleviating effects of probiotic Leuconostoc mesenteroides strains are unknown. Therefore, this study investigated the potentials of eleven L. mesenteroides strains on the Th1/Th2 balance in vitro by evaluating the expression patterns of interferon-gamma (IFN-γ) (Th1 cytokine) and interleukin-4 (IL-4) (Th2 cytokine) in mesenteric lymph node-derived lymphocytes from ovalbumin (OVA)-sensitized mice. Among strains, WHH1141 incubation caused the highest IFN-γ/IL-4 ratio. Oral administration of WHH1141 (1×109 CFU/mL) in the OVA-induced FA mouse model for 40 days improved the weight loss and FA pathological symptoms and normalized the serum immunoglobulin E levels. Meanwhile, the OVA-induced elevated gene expressions of cytokines (IL-4, IL-5, and IL-13) and tight-junction proteins (ZO-1 and Occludin) and levels of cytokines (IL-4, IL-5, and IL-13) and histamine in the jejunum were restored by WHH1141. Furthermore, WHH1141 reversed the reduced gut microbial diversity and short-chain fatty acid (SCFA) levels, specifically increased Bacteroidota abundance, and decreased Firmicutes abundance in OVA-induced mice. Overall, these findings suggest that WHH1141 exerts FA-alleviating effects on OVA-induced mice, which is involved with the inhibition of the jejunal Th2 immune responses and the modulation of gut microbiome composition and SCFA productions. PRACTICAL APPLICATION: Leuconostoc mesenteroides WHH1141 with FA-alleviating potentials may be considered a promising approach in the mitigation of FA symptoms.

A mouse model of food allergy permitting skin and nasal symptoms

PurposeDeveloping experimental animal models that show clinical symptoms and methods for quantitative and objective evaluation are important for understanding food allergies. Therefore, this study aimed to develop an ovalbumin (OVA)-induced mouse model of food allergy and a useful method to evaluate the symptoms of food allergy. Material/methodsMice were sensitized via intraperitoneal injection of OVA. Subsequently, local sensitization was performed once weekly by oral administration of OVA. Itching and nasal symptoms were observed after oral administration of the antigen. First, we examined the dose-dependency of the antigen. Symptoms were checked weekly. In order to confirm food allergy symptoms, the effect of histamine H1 receptor antagonist was examined. Finally, we measured antigen-specific IgE antibody levels in the serum. ResultsScratching behavior, sneezing and nasal rubbing were increased. Both itching and rhinitis symptoms increased steadily, after which, the number of symptoms remained almost constant. No difference was observed between the results of 3- and 5-week-old mice. Cetirizine inhibited these symptoms in a dose-dependent manner. In addition, antigen-specific IgE antibodies were produced in both 3- and 5-week-old mice. ConclusionsThis method may be useful for evaluating the symptoms of skin and rhinitis that could not be assessed in the conventional food allergy model and could be induced with a low dose of antigen. In particular, the developed method, which measures the number of itching and nasal symptoms, may enable quantitative, objective, and noninvasive evaluation of food allergy severity.

Chitinase-3-like 1 regulates TH2 cells, TFH cells and IgE responses to helminth infection.

Data from patient cohorts and mouse models of atopic dermatitis, food allergy and asthma strongly support a role for chitinase-3-like-1 protein (CHI3L1) in allergic disease. To address whether Chi3l1 also contributes to TH2 responses following nematode infection, we infected Chi3l1 -/- mice with Heligmosomoides polygyrus (Hp) and analyzed T cell responses. As anticipated, we observed impaired TH2 responses in Hp-infected Chi3l1 -/- mice. However, we also found that T cell intrinsic expression of Chi3l1 was required for ICOS upregulation following activation of naïve CD4 T cells and was necessary for the development of the IL-4+ TFH subset, which supports germinal center B cell reactions and IgE responses. We also observed roles for Chi3l1 in TFH, germinal center B cell, and IgE responses to alum-adjuvanted vaccination. While Chi3l1 was critical for IgE humoral responses it was not required for vaccine or infection-induced IgG1 responses. These results suggest that Chi3l1 modulates IgE responses, which are known to be highly dependent on IL-4-producing TFH cells.

Immune sensing of food allergens promotes avoidance behaviour

In addition to its canonical function of protection from pathogens, the immune system can also alter behaviour1,2. The scope and mechanisms of behavioural modifications by the immune system are not yet well understood. Here, using mouse models of food allergy, we show that allergic sensitization drives antigen-specific avoidance behaviour. Allergen ingestion activates brain areas involved in the response to aversive stimuli, including the nucleus of tractus solitarius, parabrachial nucleus and central amygdala. Allergen avoidance requires immunoglobulin E (IgE) antibodies and mast cells but precedes the development of gut allergic inflammation. The ability of allergen-specific IgE and mast cells to promote avoidance requires cysteinyl leukotrienes and growth and differentiation factor 15. Finally, a comparison of C57BL/6 and BALB/c mouse strains revealed a strong effect of the genetic background on the avoidance behaviour. These findings thus point to antigen-specific behavioural modifications that probably evolved to promote niche selection to avoid unfavourable environments.

Galectin-9 in synergy with NF-κB inhibition restores immune regulatory capability in dendritic cells of subjects with food allergy.

The pathogenesis of immune tolerance disruption is not fully understood. Galectin-9 (Gal9) has immune regulatory functions. The objective of the present study is to assess the role of Gal9 in maintaining immune tolerance. Blood and intestinal biopsies were taken from patients with food allergy (FA). The status of tolerogenic dendritic cells (tDC) and type 1 regulatory T cells (Tr1 cells) in the samples was evaluated and used as representative parameters of immune tolerance. An FA mouse model was established to assess the role of Gal9 in maintaining immune tolerance. We found that peripheral CD11c+ CD5+ CD1d+ tDC frequency was significantly lower in FA patients as compared to health control (HC) subjects. There was no significant change in CD11c+ DC frequency between the FA group and the HC group. The expression of IL-10 in peripheral tDCs was lower in the FA group than that in the HC group. A positive correlation was detected between the serum levels of IL-10 and Gal9. The expression of Gal9 was observed in intestinal biopsies, which was positively correlated with the serum levels of Gal9 as well as serum IL-10 levels. Peripheral Tr1 cells had lower frequencies in the FA group than in the non-FA (Con) group. tDCs demonstrated the ability to generate Tr1 cells, which was weaker in the FA group as compared with the Con group. Exposure of FA tDCs to Gal9 in culture restored the ability to generate Tr1 cells. In summary, the lower frequency of tDC and Tr1 cell of FA patients was associated with the levels of Gal9. The presence of Gal9 restored the capacity of tDC to generate Tr1 cells.

Histamine 3 receptor antagonism mitigates neuroinflammation and depression-like behavior in a mouse model of food allergy

Abstract Histamine (HA) is a major allergic response mediator as well as a neuromodulatory neurotransmitter and a blood-brain barrier (BBB) regulator. Consequently, dysregulation of the central histaminergic system could offset brain homeostasis and function. Indeed, mood and behavioral disorders are often comorbid with conditions that elevate systemic HA, such as mastocytosis and allergy. We have previously shown elevated levels of brain HA and its receptor subtype H3 (H3R) in a mouse model of cow’s milk allergy (CMA). Additionally, neuroinflammation and cortical demyelination were observed in association with depression-like behavior in CMA mice. However, whether the elevated HA and H3R were responsible for the development of these cellular and behavioral pathologies is unknown. We hypothesized that the elevated brain HA leads to central histaminergic dysfunction through H3R, ultimately resulting in cortical demyelination and aberrant behaviors. To investigate the role of H3R, CMA mice were treated daily with thioperamide, a selective BBB-permeable H3R antagonist, to block the action of HA through this receptor. Despite the production of allergen-specific IgE, thioperamide prevented depression-like behavior. Thioperamide also ameliorated CMA-associated cortical demyelination and axonal loss compared to saline-treated mice. Our findings strongly suggested that H3R signaling contributed to cortical demyelination and the development of depression-like behaviors in our CMA mice. Targeting HA production or signaling may provide a therapeutic strategy to reduce the risk of neurodegeneration and associated brain dysfunction in susceptible individuals. Supported by grants from NIH (1R01AI168563-01, P20GM113123-06, and P20GM103442).