tretinoin and Food-Hypersensitivity

Dendritic cells (DCs) mediate tolerance to food antigens, limit reactivity to the gut microbiota and are required for optimal response to intestinal pathogens. Intestinal DCs are heterogeneous but collectively generate both regulatory and effector T cell responses. The balance of outcomes is determined by the activity of functionally distinct DC subsets and their modulation by environmental cues. DCs constantly sample luminal content to monitor for pathogens; the significance of the various pathways by which this occurs is incompletely understood. Intestinal DC have distinctive properties shaped by local host, dietary and microbial signals. These properties include the ability to produce all-trans retinoic acid (RA) and imprint gut tropism on T cells they activate. In the steady-state, subsets of intestinal DC are potent generators of inducible Treg, aided by their ability to activate TGFβ and produce RA. However, responses induced by steady-state intestinal DCs are not exclusively regulatory in nature; effector T cells with specificity for commensal bacterial can be found in the healthy mucosa and these can be locally controlled to prevent inflammation. The ability of intestinal DCs to enhance effector responses in infection or sustain inflammation in disease is likely to involve both modulation of the local DC population and recruitment of additional populations. Immune pathways in the pathogenesis of inflammatory bowel disease can be mapped to DCs and in inflamed intestinal tissue, DCs show increased expression of microbial recognition machinery, activation, and production of key immunological mediators. Intestinal DCs may be targeted for disease therapy or to improve vaccine responses.

Topics: Allergens; Animals; Cell Communication; Colitis; Dendritic Cells; Disease Models, Animal; Food Hypersensitivity; Gastrointestinal Microbiome; Humans; Immunity, Mucosal; Immunologic Factors; Intestinal Mucosa; Intraepithelial Lymphocytes; T-Lymphocytes, Cytotoxic; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Tretinoin

Allergic reactions to food can significantly reduce the quality of life and even result in life-threatening complications. In addition, the prevalence of food allergy has increased in the last decades in industrialized countries and the mechanisms underlying (increased) sensitization are still not fully understood. It is believed that the development and maintenance of oral tolerance to food antigens is a process actively mediated by the immune system and that this reaction is essential to inhibit sensitization. Ongoing research indicates that different dietary factors also may contribute to immune homeostasis and oral tolerance to food and that food processing modulates allergenicity. One of the major questions in food allergy research is therefore which impact nutrition and food processing may have on allergenicity of food and perhaps on sensitization. We summarize in this review the different dietary factors that are believed to contribute to induction of oral tolerance and discuss the underlying mechanisms. In addition, the functional consequences of allergen modification will be emphasized in the second part as severity of allergic reactions and perhaps sensitization to food is influenced by structural modifications of food allergens.

Topics: Allergens; Antigens; Diet; Dietary Fiber; Fatty Acids, Unsaturated; Food Handling; Food Hypersensitivity; Humans; Polyphenols; Prebiotics; Tretinoin; Vitamin E

Food allergy is a serious and growing problem. Although the current standard of care for patients with food allergies is based on avoidance of the trigger, increased understanding of the mechanisms involved in oral tolerance has shifted focus of treatment and prevention toward inducing tolerance. Here we discuss the relationship of food allergy to oral tolerance and review recent oral tolerance studies, focusing on the mechanistic role of antigen presenting cells and the generation of regulatory T cells in mice and humans.. Specialized intestinal antigen presenting cells are conditioned by spatial and soluble microenvironmental factors to promote tolerance to dietary antigen primarily via the induction of regulatory T cells. Retinoic acid, a vitamin A metabolite, has been recently identified as a key environmental factor in this process.. Future clinical trials for food allergy immunotherapy will benefit from approaches, which target the oral tolerance pathways currently being elucidated.

Topics: Administration, Oral; Allergens; Animals; Antigen-Presenting Cells; Clinical Trials as Topic; Desensitization, Immunologic; Dietary Proteins; Food Hypersensitivity; Humans; Immune Tolerance; Immunologic Factors; Mice; Monitoring, Immunologic; T-Lymphocytes, Regulatory; Tretinoin

Alteration of commensal microbiota is highly correlated with the prevalence of allergic reactions to food in the gastrointestinal tract. The mechanisms by which microbiota modulate food allergen sensitization in the mucosal site are not fully understood.. We generate DCs specific knockout of retinoic acid receptor α (Rara) gene mice (DC KO Rara) to evaluate food sensitization. The bile acid-activated retinoic acid response was evaluated by flow cytometry, real-time RT-PCR and Illumina transcriptome sequencing. The global effect of Abx treatment on BA profiles in the mucosal lymph tissue mLN in mice was examined by UPLC-MS analysis.. In this study, we demonstrate that depletion of commensal gut bacteria leads to enhanced retinoic acid (RA) signaling in mucosal dendritic cells (DCs). RA signaling in DCs is required for the production of food allergen-specific IgE and IgG1. Antibiotics induced an enlarged bile acid (BA) pool, and dysregulated BA profiles contributed to enhanced RA signaling in mucosal DCs. BA-activated RA signaling promoted DC upregulation of interferon I signature, RA signature, OX40L, and PDL2, which may lead to T helper 2 differentiation of CD4+ T cells. BA-activated RA signaling involved the farnesoid X receptor and RA receptor α (RARa) interaction. Depletion of bile acid reduces food allergen specific IgE and IgG1 levels in mice.. Our research unveils a mechanism of food sensitization modulated by BA-RA signaling in DCs, which suggests a potential new approach for the intervention of food allergic reactions.

Topics: Allergens; Animals; Bile Acids and Salts; Chromatography, Liquid; Dendritic Cells; Food Hypersensitivity; Humans; Immunoglobulin E; Immunoglobulin G; Mice; Tandem Mass Spectrometry; Tretinoin

Gut-microbiota dysbiosis links to allergic diseases. The mechanism of the exacerbation of food allergy caused by gut-microbiota dysbiosis remains unknown. Regulation of retinoic acid receptor alpha (RARα) signaling is critical for gut immune homeostasis. Here we clarified that RARα in dendritic cells (DCs) promotes Th2 cell differentiation. Antibiotics treatment stimulates retinoic acid signaling in mucosal DCs. We found microbiota metabolites short-chain fatty acids (SCFAs) maintain IGF-1 levels in serum and mesenteric lymph nodes. The IGF-1/Akt pathway is essential for regulating the transcription of genes targeted by RARα. And RARα in DCs affects type I interferon (IFN-I) responses through regulating transcription of IFN-α. Our study identifies SCFAs crosstalk with RARα in dendritic cells as a critical modulator that plays a core role in promoting Th2 cells differentiation at a state of modified/disturbed microbiome.

Topics: Animals; Anti-Bacterial Agents; Bacteria; Cells, Cultured; Dendritic Cells; Disease Models, Animal; Dysbiosis; Fatty Acids, Volatile; Food Hypersensitivity; Gastrointestinal Microbiome; Insulin-Like Growth Factor I; Interferon Type I; Mice, Inbred C57BL; Mice, Knockout; Proto-Oncogene Proteins c-akt; Retinoic Acid Receptor alpha; Signal Transduction; Th2 Cells; Tretinoin

Effectiveness of retinoic acid (RA) in treating food allergy is not yet clear. Using an allergic mouse model, we examined the amelioration of the severity of food allergy by daily RA intake with allergen or without. Female Balb/c mice were systemically sensitized to egg white (EW) and alum by intraperitoneal injection. Sensitized mice were provided diets supplemented with 0% (non-treated group), 0.1% EW (allergen group), 0.0017% RA (RA group), or 0.1% EW plus 0.0017% RA (RA+allergen group) with 20% casein for 4 wk. Oral food challenge (OFC) and allergic biomarkers were quantified. The decrease in rectal temperature post-OFC was significantly suppressed in the RA and RA+allergen groups compared to those in the non-treated and allergen groups, respectivety. The plasma levels of ovalbumin-specific IgE, IgA and IgG1 at the study endpoint were higher in the allergen and RA+allergen groups than those in the non-treated and RA+allergen groups, respectivety. Plasma ovalbumin-specific IgG2a levels at the study endpoint were significantly higher in the RA+allergen group than those in the RA groups. The supernatant concentrations of interleukin-10 and interferon-γ in the cultured spleen lymphocytes were highest in the RA+allergen group compared to those in the other groups. Thus, continuous intake of RA under allergen exposure ameliorated the severity of food allergy in a mouse model with food allergy.

Topics: Allergens; Animals; Body Temperature; Dietary Supplements; Disease Models, Animal; Egg Hypersensitivity; Egg White; Female; Food Hypersensitivity; Immunoglobulin A; Immunoglobulin E; Immunoglobulin G; Interferon-gamma; Interleukin-10; Lymphocytes; Mice; Mice, Inbred BALB C; Ovalbumin; Tretinoin

The disruption of intestinal mucosal immune tolerance can lead to the development of intestinal immune diseases such as food allergy (FA). Regulatory T cells (Tregs) in the mucosa play a critical role in maintaining peripheral immune tolerance in the intestine, and retinoic acid (RA) is absolutely required for the induction of Tregs. We have previously reported that kakkonto, a traditional Japanese herbal medicine, suppresses FA in a murine FA model due to the induction of Tregs in the colonic mucosa. However, the precise molecular mechanisms underlying the induction of Tregs remain unclear. Puerarin, an isoflavone derivative, is a major constituent of kakkonto. Thus, we investigated the effect of puerarin on the induction of Tregs. BALB/c mice were systemically sensitized and then orally challenged with ovalbumin (OVA) as an FA model. Puerarin treatment suppressed the development of allergic diarrhea in FA mice. The gene expression levels of IL-4 and mast cell protease I (mMCP-1) were significantly upregulated in the proximal colon of FA mice but were reduced by puerarin. The proportions of Foxp3

Topics: Animals; Cells, Cultured; Dendritic Cells; Disease Models, Animal; Food Hypersensitivity; Forkhead Transcription Factors; Immune Tolerance; Intestinal Mucosa; Isoflavones; Mice, Inbred BALB C; Mice, Knockout; Mice, Transgenic; T-Lymphocytes, Regulatory; Tretinoin; Vasodilator Agents

The present study extends an earlier report that retinoic acid (RA) down-regulates IgE Ab synthesis in vitro. Here, we show the suppressive activity of RA on IgE production in vivo and its underlying mechanisms. We found that RA down-regulated IgE class switching recombination (CSR) mainly through RA receptor α (RARα). Additionally, RA inhibited histone acetylation of germ-line ε (GL ε) promoter, leading to suppression of IgE CSR. Consistently, serum IgE levels were substantially elevated in vitamin A-deficient (VAD) mice and this was more dramatic in VAD-lecithin:retinol acyltransferase deficient (LRAT

Topics: Acyltransferases; Animals; Chymases; Food Hypersensitivity; Immunoglobulin Class Switching; Immunoglobulin E; Interleukin-4; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Retinoic Acid Receptor alpha; T-Lymphocytes, Regulatory; Tretinoin; Vitamin A; Vitamin A Deficiency

Topics: Acne Vulgaris; Adult; Alitretinoin; Clinical Protocols; Dermatologic Agents; Female; Food Hypersensitivity; Glycine max; Humans; Isotretinoin; Nut Hypersensitivity; Tretinoin

The incidence of food allergy has increased in recent years and there is no effective way to treat it except strict dietary avoidance and rapid medical treatment in case of accidental exposure. Oral tolerance, as a new method, has shown great promise as an alternative approach to prevention and treatment for allergic disease. It was reported that all-trans retinoic acid (atRA) plays an important role in inducing oral tolerance in vitro. Our study aimed to investigate the immunological effect of different doses of atRA on ovalbumin (OVA) allergic BALB/c mice.. BALB/c mice were sensitized by intraperitoneal injection with OVA to establish allergic animal model. According to the dose of atRA given, 40 OVA allergic BALB/c mice were divided into 4 groups: the mice in high dose group were treated with 100 mg/kg atRA (atRA-H), those in median dose group were treated with 50 mg/kg atRA (atRA-M), those in low dose group were treated with 20 mg/kg atRA (atRA-L) and the mice in control group were given vehicle-soy oil only (CTR). After 12 days of atRA intervention, weight was measured, the mice were checked for diarrhea , and intestinal histology was observed after hematoxylin and eosin staining. The level of OVA-IgE in serum, total IgA and OVA-IgA in feces were measured by ELISA. The percentage of CD4⁺ CD25⁺ FoxP3⁺ T cells in CD4⁺ T cells in mesenteric lymph node was detected by flow cytometry.. Compared with that of CTR group, the level of OVA-IgE in serum (1.221 ± 0.367 vs. 0.793 ± 0.616) and OVA-IgA (1.573 ± 0.656 vs. 0.905 ± 0.279) in feces decreased significantly (P = 0.006 and 0.012, respectively) without weight and intestinal histology changes after low dose of atRA administration. However, there was no significant difference in the percentage of CD4⁺ CD25⁺ FoxP3⁺ T cells in CD4⁺ T cells in mesenteric lymph node (10.641 ± 1.218 vs. 10.936 ± 0.954) between atRA-L and CTR group (P > 0.05). While in animals with high and median dose of atRA administration, no immunologic improvement was found, instead, there was weight loss and intestinal mucosal damage.. Low dose of atRA intervention seems to induce immune suppression in vivo resulting in positive effects on OVA allergic mice. However, median and high dose atRA had no therapeutic effect on OVA allergic mice.

Topics: Animals; CD4-Positive T-Lymphocytes; Food Hypersensitivity; Immune Tolerance; Lymph Nodes; Mice; Mice, Inbred BALB C; Ovalbumin; T-Lymphocytes, Regulatory; Tretinoin