Mechanism of oral tolerance / 国际儿科学杂志

Oral tolerance is a state of no or low response to a specific oral antigen,but there are still normal immune responses to other antigens.Anaphylaxis may occur when oral tolerance is not established or destroyed.In recent years,the incidence of food allergy in Chinese children has increased,with an average of 5.83 ％ reported by parents.Therefore,it is of great significance to explore the mechanisms of oral tolerance.The mechanisms of oral tolerance include active suppression,bypass suppression,clonal anergy/deletion.Oral administration of low-dose antigen can induce regulatory T cells to secrete inhibitory cytokines and actively inhibit effector T cells.Oral administration of high-dose antigen can induce clonal anergy/deletion.Regulatory B cells,dendritic cells,various cytokines,gut microbiota and short-chain fatty acids also play an important role in oral tolerance.This review focuses on the mechanism and some influencing factors of oral tolerance.

Cow's milk oral immunotherapy in real life: 8-year long-term follow-up study

BACKGROUND: Oral immunotherapy (OIT) has been recognized as a promising treatment for severe and long-lasting cow's milk (CM) allergy. Once maintenance has been achieved, patients should maintain daily intake of CM to ensure desensitization. Clinical experience concerning long-term follow-up is scarce. OBJECTIVE: The authors aimed to assess long-term efficacy and safety of a maintenance phase of OIT in real life. METHODS: Prospective study of all children and adolescents, who underwent CM-OIT and were subsequently followed at our allergy center on maintenance dose (200 mL daily) for at least 36 months after reaching the maintenance phase (from 2009 to 2016). RESULTS: Forty-two patients were enrolled: 60% male, 36% with history of anaphylaxis and 57% with asthma. The median time of follow-up was 69 months (range, 39–105 months) and the median age at the last clinical evaluation was 13 years (range, 6–23 years). Regarding adherence to the protocol: 92% are on free diet (at least 200 mL of CM daily; 7-g protein); 14% had transient interruptions and 7% definitely withdrawn with loss of tolerance. During maintenance, 45% developed mild to severe allergic reactions, and 7% had more than 3 episodes. A positive correlation between the occurrence of allergic reactions and history of anaphylaxis (p < 0.001) was found. The coexistence of asthma was risk factor for the occurrence of allergic reactions during maintenance. CONCLUSION: This real-life study supports long-term efficacy and safety of CM-OIT. Despite daily intake, 41% had symptoms at some moment during the complete follow-up period; a total of 33 symptomatic days in patients with mean follow-up time of 67.5 months. Clinical tolerance depends on daily intake. The protective effect reached can be lost after CM withdrawal. History of anaphylaxis was a risk factor for the occurrence of allergic reactions during the maintenance phase.

Un caso inusual de síndrome de enterocolitis inducida por proteínas alimentarias / Unusual case of food protein-induced enterocolitis syndrome

El síndrome de enterocolitis inducido por proteínas alimentarias es un síndrome de hipersensibilidad gastrointestinal a alimentos no mediado por inmunoglobulina E, que, en su forma aguda, se manifiesta con vómitos repetitivos, palidez e hipotonía, que puede acompañarse o no de diarrea y producir un cuadro grave de deshidratación y letargia. Una prueba de provocación oral controlada es, en ocasiones, realizada para confirmar el diagnóstico y el tratamiento consiste en la eliminación del alimento causante. Se presenta el caso de un lactante de 3 meses con varios episodios de síndrome de enterocolitis tras la toma de biberón de leche de fórmula de inicio con tolerancia de otra marca comercial. Se encontraron diferencias en los ingredientes de su composición que podrían ser el origen de la sensibilización.

Food protein-induced enterocolitis syndrome is a nonimmunoglobulin E mediated gastrointestinal food hypersensitivity that manifests as profuse, repetitive vomiting, pallor and hypotonia, often with diarrhea leading to severe dehydration and lethargy (sepsis-like symptoms) in the acute setting. An oral food challenge is sometimes performed to confirm the diagnosis and treatment consists of elimination of the food trigger(s) from the diet. We report a case of a 3-months-old infant with several episodes of food protein-induced enterocolitis syndrome after taking infant formula milk with tolerance of another trademark. Differences in the composition of its ingredients could be the cause of the sensitization.

Anti-Interleukin-9 Antibody Increases the Effect of Allergen-Specific Immunotherapy in Murine Allergic Rhinitis

PURPOSE: Interleukin (IL)-9 induces allergic responses; however, the roles of anti-IL-9 antibody in the induction of tolerance remain unclear. This study investigated the effects of anti-IL-9 antibody on oral tolerance (OT) in a mouse model of allergic rhinitis (AR). METHODS: BALB/c mice were divided into 4 groups: the control, AR, OT, and OT with anti-IL-9 antibody (OT+IL9AB) groups. Ovalbumin (OVA) was used for sensitization and challenge. Mice in the OT and OT+IL9AB groups were fed OVA for immunotherapy. During immunotherapy, OT+IL9AB mice were injected with anti-IL-9 antibody. Allergic symptoms, tissue eosinophil counts, and serum OVA-specific immunoglobulin E (IgE) were measured. The mRNA expressions of cytokines and transcription factors of T cells of nasal mucosa were determined by real-time polymerase chain reaction (PCR). The protein levels of GATA3, ROR-γt, and Foxp3 in nasal mucosa were determined by Western blot. CD4⁺CD25⁺Foxp3⁺ T cells in the spleen were analyzed by flow cytometry. RESULTS: Administration of anti-IL-9 antibody decreased allergic symptoms, OVA-specific IgE levels, and eosinophil counts. In addition, it inhibited T-helper (Th) 2 responses, but had no effect on Th1 responses. Protein levels of ROR-γt and mRNA levels of PU.1 and ROR-γt were reduced by anti-IL-9 antibody. Anti-IL-9 antibody increased Foxp3 and IL-10 mRNA expression, Foxp3 protein, and induction of CD4⁺CD25⁺Foxp3⁺ T cells. CONCLUSIONS: Anti-IL-9 antibody decreased allergic inflammation through suppression of Th2 and Th17 cells. Anti-IL-9 antibody enhanced the tolerogenic effects of regulatory T cells. These results suggest that anti-IL-9 antibody might represent a potential therapeutic agent for allergen immunotherapy in patients with uncontrolled allergic airway disease.

Role of Regulatory Cells in Oral Tolerance

The immune system is continuously exposed to great amounts of different antigens from both food and intestinal microbes. Immune tolerance to these antigens is very important for intestinal and systemic immune homeostasis. Oral tolerance is a specific type of peripheral tolerance induced by exposure to antigen via the oral route. Investigations on the role of intestinal immune system in preventing hypersensitivity reactions to innocuous dietary and microbial antigens have been intensively performed during the last 2 decades. In this review article, we discuss how food allergens are recognized by the intestinal immune system and draw attention to the role of regulatory T (Treg) and B (Breg) cells in the establishment of oral tolerance and tolerogenic features of intestinal dendritic cells. We also emphasize the potential role of tonsils in oral tolerance induction because of their anatomical location, cellular composition, and possible usage to develop novel ways of specific immunotherapy for the treatment of allergic diseases.

3,3'-Diindolylmethane Inhibits Flt3L/GM-CSF-induced-bone Marrow-derived CD103+ Dendritic Cell Differentiation Regulating Phosphorylation of STAT3 and STAT5

The intestinal immune system maintains oral tolerance to harmless antigens or nutrients. One mechanism of oral tolerance is mediated by regulatory T cell (Treg)s, of which differentiation is regulated by a subset of dendritic cell (DC)s, primarily CD103+ DCs. The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, plays an important role in regulating immunity. The intestines are exposed to various AhR ligands, including endogenous metabolites and phytochemicals. It was previously reported that AhR activation induced tolerogenic DCs in mice or in cultures of bone marrow-derived DCs. However, given the variety of tolerogenic DCs, which type of tolerogenic DCs is regulated by AhR remains unknown. In this study, we found that AhR ligand 3,3'-diindolylmethane (DIM) inhibited the development of CD103+ DCs from mouse bone marrow cells stimulated with Flt3L and GM-CSF. DIM interfered with phosphorylation of STAT3 and STAT5 inhibiting the expression of genes, including Id2, E2-2, IDO-1, and Aldh1a2, which are associated with DC differentiation and functions. Finally, DIM suppressed the ability of CD103+ DCs to induce Foxp3+ Tregs.

Desarrollo de tolerancia oral en niños con alergia a la proteína de leche de vaca: seguimiento de 10 años / Oral tolerance development in children with allergy to cow's milk protein: follow-up of 10 years

Se estima que niños alérgicos desarrollen tolerancia oral durante los primeros años de vida con una dieta de eliminación de lácteos. Determinar el tiempo de desarrollo de tolerancia oral a la proteína de leche de vaca, características clínicas y laboratorio. Estudio prospectivo, seguimiento durante 10 años, de niños con alergia a proteína de leche de vaca. Se indicó dieta de eliminación por 4 semanas con posterior reto. Se solicitó IgE total y específica. Se registro edad y tiempo de dieta al confirmarse la tolerancia. 81 niños, 33/81(40,74%) femeninos y 48/81(59,25%) masculinos, edad promedio de diagnóstico 6,22 meses(rango <1-42). Alergia no mediada IgE 32/81 (39,50%) y alergia mediada IgE 49/81 (60,49%); IgE específica para leche de vaca positivo en 55/81 (67,90%). Diagnóstico por respuesta positiva a la dieta de eliminación en 62/81 (76,54%) y con reto en 19/81 (23,45%). Desarrollaron tolerancia después de 12-18m con dieta, 21/32 (65,62%) con alergia no IgE a los 1,6 años y 23/49 (46,93%) con alergia IgE a los 2,13 años. Los niños restantes toleraron entre 19-24m, a los 2,35 y 2,80 años para la alergia no IgE e IgE respectivamente. Después de 36m, continuaron sin tolerar 5 niños entre ambos grupos con progreso a alergia alimentaria múltiple. El diagnóstico de alergia puede basarse en la respuesta positiva a la dieta de eliminación de lácteos, el reto es necesario en casos inciertos y la tolerancia se alcanza a una edad más temprana en niños con alergia no mediada IgE

It is estimated that allergic children develop oral tolerance in the early years of life with a dairy elimination diet. To determine the time development of oral tolerance to cow's milk protein, clinical and laboratory. A prospective study followed for 10 years, children allergic to cow's milk protein. He said elimination diet for 4 weeks after challenge. Was requested total IgE and specific. Age and time was recorded to confirm diet tolerance. 81 children, 33/81 (40.74%) were female and 48/81 (59.25%) male, average age at diagnosis 6.22 months (range <1-42). IgE-mediated allergy is not 32/81 (39.50%) and IgE-mediated allergy 49/81 (60.49%) specific IgE to cow's milk positive in 55/81 (67.90%). Diagnosis by positive response to the elimination diet in 62/81 (76.54%) and challenge in 19/81 (23.45%). Tolerance developed after 12-18m with diet, 21/32 (65.62%) with non-IgE allergy to 1.6 years and 23/49 (46.93%) with IgE allergy to 2.13 years. The remaining children tolerated between 19-24m, to the 2.35 and 2.80 years for non-IgE allergy and IgE, respectively. After 36m, continued without tolerating 5 children between the two groups with multiple food allergy progress. The diagnosis of allergy can be based on positive response to milk elimination diet, the challenge is necessary in uncertain cases and tolerance is reached at an earlier age in children with IgE mediated allergy is not

Effect of aging and oral tolerance on dendritic cell function

Oral tolerance can be induced in some mouse strains by gavage or spontaneous ingestion of dietary antigens. In the present study, we determined the influence of aging and oral tolerance on the secretion of co-stimulatory molecules by dendritic cells (DC), and on the ability of DC to induce proliferation and cytokine secretion by naive T cells from BALB/c and OVA transgenic (DO11.10) mice. We observed that oral tolerance could be induced in BALB/c mice (N = 5 in each group) of all ages (8, 20, 40, 60, and 80 weeks old), although a decline in specific antibody levels was observed in the sera of both tolerized and immunized mice with advancing age (40 to 80 weeks old). DC obtained from young, adult and middle-aged (8, 20, and 40 weeks old) tolerized mice were less efficient (65, 17 and 20 percent, respectively) than DC from immunized mice (P < 0.05) in inducing antigen-specific proliferation of naive T cells from both BALB/c and DO11.10 young mice, or in stimulating IFN-g, IL-4 and IL-10 production. However, TGF-â levels were significantly elevated in co-cultures carried out with DC from tolerant mice (P < 0.05). DC from both immunized and tolerized old and very old (60 and 80 weeks old) mice were equally ineffective in inducing T cell proliferation and cytokine production (P < 0.05). A marked reduction in CD86+ marker expression was observed in DC isolated from both old and tolerized mice (75 and 50 percent, respectively). The results indicate that the aging process does not interfere with the establishment of oral tolerance in BALB/c mice, but reduces DC functions, probably due to the decline of the expression of the CD86 surface marker.

Food allergy: recent advances in pathophysiology and treatment

Food allergies are adverse immune reactions to food proteins that affect up to 6% of children and 3-4% of adults. A wide range of symptoms can occur depending on whether IgE or non-IgE mediated mechanism are involved. Many factors influence the development of oral tolerance, including route of exposure, genetics, age of the host, and allergen factors. Advances have been made in the understanding of how these factors interact in the pathophysiology of food allergy. Currently, the mainstay of treatment for food allergies is avoidance and ready access to emergency medications. However, with the improved understanding of tolerance and advances in characterization of food allergens, several therapeutic strategies have been developed and are currently being investigated as potential treatments and/or cures for food allergy.

Food allergy: recent advances in pathophysiology and treatment

Food allergies are adverse immune reactions to food proteins that affect up to 6% of children and 3-4% of adults. A wide range of symptoms can occur depending on whether IgE or non-IgE mediated mechanism are involved. Many factors influence the development of oral tolerance, including route of exposure, genetics, age of the host, and allergen factors. Advances have been made in the understanding of how these factors interact in the pathophysiology of food allergy. Currently, the mainstay of treatment for food allergies is avoidance and ready access to emergency medications. However, with the improved understanding of tolerance and advances in characterization of food allergens, several therapeutic strategies have been developed and are currently being investigated as potential treatments and/or cures for food allergy.

Food Allergy in Children

Food allergy has increased in developed countries over the past 20 years and it has been estimated that food allergic reactions affect some 6~8% of children. Food allergy is common and potentially serious problem in childhood. Adverse reaction to food could be classified into four groups: IgE-mediated food allergy; non-IgE mediated food allergy; non-allergic food hypersensitivity; and symptoms falsely assumed to be due to foods. Allergic testing is moving towards established thresholds levels of specific IgE that predict a probability of a clinical reaction and reduce the need of oral food challenge. 1) Diagnosing and managing food allergy in children largely depends upon a thorough medical history with questions targeted to differentiate the character of the reaction for each suspected food. 2) Investigations such as skin prick testing and specific IgE are helpful only in IgE-mediated reactions. 3) The mainstay of management is to avoid the offending allergen. 4) An anaphylactic reaction is an indication for self-injectable epinephrine for emergency use. Studies of allergen characterization and immunologic mechanisms are needed and should provide a better understanding of the immunopathology of food allergy and new, more specific forms of diagnosis and therapy. It is important to identify children with potentially life-threatening food allergy as life-threatening reaction can occur. A clear understanding of the manifestations of food allergy caused by both IgE- and non-IgE-related mechanisms will help the practitioner to identify children who likely have food allergy so that additional diagnostic evaluation can be performed and appropriate avoidance can be instituted.

Increased Indoleamine 2,3-Dioxygenase Expressing CD11c+ CD11b+ Dendritic cells in Oral Tolerance to Type II Collagen / 대한류마티스학회지

OBJECTIVE: Indoleamine 2, 3-dioxygenase (IDO), an immuno suppression enzyme, is one of the initial and rate-limiting enzymes involved in the catabolism of the essential amino acid tryptophan. IDO inhibits T cell proliferation, induces T cell apoptosis, and plays a fundamental role in autoimmunity and allergy. We investigated which subtype of dendritic cells (DCs) is involved in IDO expression and the generation of regulatory T cells during the induction of oral tolerance in type II collagen-induced arthritis (CIA). METHODS: Type II Collagen was fed to DBA/1J mice before immunization. Changes in DC subtypes and induction of regulatory T cell in orally tolerized CIA mice were analyzed. Whether the effect of DC subtype was modulated by the IDO expression, was determined by flow cytometry (FACs) and confocal microscopy. RESULTS: IDO expression of CD11c+ DCs was higher in orally tolerized CIA mice than in non-tolerized CIA mice. CD11b+ DCs of the CD11c +DCs, subtype was higher in the induction of in IDO expression. Our data suggest that these IDO expressing DCs of oral tolerized mice suppressed type II collagen-specific T cell proliferation and favored the differentiation of naive CD4+ T cells into regulatory T cells. Especially, CD11c+CD11b+ DCs expressed IDO, which is known to be associated with regulatory T cell induction. CONCLUSION: We observed that oral tolerance induced the increase in IDO-expressing CD11c+CD11b+ DCs, which appeared to induce regulatory T cells. IDO-expressing CD11c+CD11b+ DCs are involved in oral tolerance, which may provide a new therapeutic approach for the treatment of rheumatoid arthritis.

A Co-inhibitory Molecule, B7-H4, Synergistically Potentiates Oral Tolerance by Inducing CD4+CD25+FoxP3+ T Cells

BACKGROUND: A co-inhibitory molecule, B7-H4, is believed to negatively regulate T cell immunity by suppressing T cell proliferation and inhibiting cytokine production. However, the mechanism behind B7-H4-mediated tolerance remains unclear. METHODS: Balb/c (H-2(d)) mice were fed with dendritic cell line, DC2.4 (H-2(b)) every day for 10 days. Meantime, mice were hydrodynamically injected with recombinant plasmid expressing B7-H4 fusion protein (B7-H4.hFc) or hFc via tail vein. One day after last feeding, mice were immunized with allogeneic B6 spleen cells. 14 days following immunization, mice were challenged with B6 spleen cells to ear back and the ear swelling was determined the next day. Subsequently, a mixed lymphocyte reaction (MLR) was also performed and cytokines profiles from the reaction were examined by sandwich ELISA. Frequency of immunosuppressive cell population was assayed with flow cytometry and mRNA for FoxP3 was determined by RT-PCR. RESULTS: Tolerant mice given plasmid expressing B7-H4.hFc showed a significant reduction in ear swelling compared to control mice. In addition, T cells from mice given B7-H4.hFc plasmid revealed a significant hyporesponsiveness of T cells against allogeneic spleen cells and showed a significant decrease in Th1 and Th2 cytokines such as IFN-gamma, IL-5, and TNF-alpha. Interestingly, flow cytometric analysis showed that the frequency of CD4+CD25+FoxP3+ Tregs in spleen was increased in tolerant mice given recombinant B7-H4.hFc plasmid compared to control group. CONCLUSION: Our results demonstrate that B7-H4 synergistically potentiates oral tolerance induced by allogeneic cells by increasing the frequency of FoxP3+ CD4+CD25+ Treg and reducing Th1 and Th2 cytokine production.

A Co-inhibitory Molecule, B7-H4, Synergistically Potentiates Oral Tolerance by Inducing CD4+CD25+FoxP3+ T Cells

BACKGROUND: A co-inhibitory molecule, B7-H4, is believed to negatively regulate T cell immunity by suppressing T cell proliferation and inhibiting cytokine production. However, the mechanism behind B7-H4-mediated tolerance remains unclear. METHODS: Balb/c (H-2(d)) mice were fed with dendritic cell line, DC2.4 (H-2(b)) every day for 10 days. Meantime, mice were hydrodynamically injected with recombinant plasmid expressing B7-H4 fusion protein (B7-H4.hFc) or hFc via tail vein. One day after last feeding, mice were immunized with allogeneic B6 spleen cells. 14 days following immunization, mice were challenged with B6 spleen cells to ear back and the ear swelling was determined the next day. Subsequently, a mixed lymphocyte reaction (MLR) was also performed and cytokines profiles from the reaction were examined by sandwich ELISA. Frequency of immunosuppressive cell population was assayed with flow cytometry and mRNA for FoxP3 was determined by RT-PCR. RESULTS: Tolerant mice given plasmid expressing B7-H4.hFc showed a significant reduction in ear swelling compared to control mice. In addition, T cells from mice given B7-H4.hFc plasmid revealed a significant hyporesponsiveness of T cells against allogeneic spleen cells and showed a significant decrease in Th1 and Th2 cytokines such as IFN-gamma, IL-5, and TNF-alpha. Interestingly, flow cytometric analysis showed that the frequency of CD4+CD25+FoxP3+ Tregs in spleen was increased in tolerant mice given recombinant B7-H4.hFc plasmid compared to control group. CONCLUSION: Our results demonstrate that B7-H4 synergistically potentiates oral tolerance induced by allogeneic cells by increasing the frequency of FoxP3+ CD4+CD25+ Treg and reducing Th1 and Th2 cytokine production.

Oral Tolerance Increased the Proportion of CD8+ T Cells in Mouse Intestinal Lamina Propria

BACKGROUND: Oral tolerance is defined by the inhibition of immune responsiveness to a protein previously exposed via the oral route. Protein antigens exposed via the oral route can be absorbed through the mucosal surfaces of the gastrointestinal tract and can make physical contact with immune cells residing in the intestinal lamina propria (LP). However, the mechanisms of oral tolerance and immune regulation in the intestines currently remain to be clearly elucidated. METHODS: In order to determine the effect of oral protein antigen intake (ovalbumin, OVA) on the intestinal LP, we assessed the expression profile of the T cell receptor and the co-receptors on the cells from the intestines of the tolerant and immune mouse groups. RESULTS: We determined that the proportion of OVA-specific B cells and gamma delta T cells had decreased, but the CD8alpha beta and CD8alpha alpha T cells were increased in the LP from the tolerant group. The proportion of CD8+ T cells in the spleen did not evidence any significant differences between treatment groups. CONCLUSION: These results indicate that CD8+ T cells in the intestinal LP may perform a regulatory role following antigen challenge via the oral route.

La modulación del sistema inmune de mucosas con polisacáridos: Bases para una atractiva alternativa en terapia / Modulation of the mucosal immune system with polysaccharides: Basis for an attractive therapeutic alternative

El sistema inmune de mucosas del intestino presenta propiedades únicas: está expuesto a una gran variedad y cantidad de antígenos, desarrolla una actividad inmunológica permanente y mantiene un microambiente fisiológicamente desviado hacia respuestas anti-inflamatorias. Es capaz de distinguir y neutralizar agentes nocivos y reconocer antígenos inocuos, generando entonces un estado de no respuesta llamado tolerancia oral. Este fenómeno natural representa una forma fisiológica, segura e inocua de manipular las respuestas inmunes, para el tratamiento de enfermedades autoinmunes, inflamatorias o alérgicas. Aquellos compuestos que presenten la habilidad de favorecer la tolerancia permitirían optimizar el desarrollo de nuevos protocolos de inmunointervención. Quitosano (Q) es un polisacárido que abunda en la naturaleza con características fisicoquímicas y biológicas particulares: carece de toxicidad y alergenicidad, es biocompatible y biodegradable, presenta propiedades mucoadhesivas que favorecen el transporte y la absorción de proteínas a través del epitelio. Tiene actividad adyuvante, aumentando los niveles de IgA en la mucosa. Estas características lo convierten en un candidato ideal para la inmunointervención a nivel de mucosas. En este trabajo se describe el mecanismo de acción del Q luego de la administración oral, demostrando por primera vez que Q contribuye a mantener la homeostasis intestinal y a modular a nivel local y sistémico las respuestas inmunes hacia un antígeno proteico. Esta caracterización ayuda a comprender cómo participa un polisacárido en la fina regulación de las respuestas de mucosa y sugiere alternativas de manipulación que permitirán el desarrollo de terapias que requieran de microambientes anti-inflamatorios.

The mucosal immune system exhibits distinctive traits: it is permanently exposed to an overwhelming amount and variety of antigens; it maintains a continuous immune activity and it sustains a physiological environment biased to anti-inflammatory responses. Although it mounts efficient responses against pathogens, it reacts to innocuous antigens developing the oral tolerance state. Oral tolerance is a natural process that can be safely applied for the treatment of autoimmune, inflammatory or allergic diseases. Compounds able to promote the tolerance phenomenon can be used to optimize the development of alternative therapies. Chitosan (Q) is a natural and abundant polysaccharide with singular biological and physico-chemical properties that make it a good candidate to modulate the mucosal immunity: non toxic, biocompatible and biodegradable, strongly mucoadhesive favoring the transepithelial absorption of proteins and adjuvant, enhancing the levels of IgA to co-administered antigens. This work describes the Q activity mechanism early after its oral administration, for the first time showing, Q´s contribution to the intestinal homeostasis and also its modulation of the immune response to a protein antigen at local and systemic level. These studies will help understand how the intestinal regulatory activity occurs, and develop new therapeutic approaches to stimulate anti-inflammatory environments at mucosal level.

Breakdown of Mucosal Immunity in Gut by 2,3,7,8-Tetraclorodibenzo-\it{p}-dioxin (TCDD)

Objectives: Mucosal immunity plays a pivotal role for body defense against infection and allergy. The aim of this study was to clarify the effects of 2,3,7,8-tetraclorodibenzo-p-dioxin (TCDD) on mucosal immunity in the gut. Methods: Fecal IgA level and oral tolerance induction were examined in TCDD-treated mice. Flow cytometric and histological analyses were also performed. Results: Single oral administration of low dose 2,3,7,8-TCDD resulted in a marked decrease in IgA secretion in the gut without any effects on the cellular components of gut-associated lymphoid tissues (GALT) including Peyer’s patches (PPs) and mesenteric lymph nodes (LNs). Decreased IgA secretion by TCDD was not observed in aryl hydrocarbon receptor (AhR)-deficient mice. Flow cytometric analysis revealed that IgA+ B cells in PPs and the mesenteric LNs remained unchanged in the TCDD-treated mice. An immunofluorescence study also demonstrated that a significant number of cytoplasmic IgA+ cells were present in the lamina propria of the gut in the TCDD-treated mice. Furthermore, oral tolerance induction by ovalbumin (OVA) was impaired in the TCDD-treated mice and OVA-specific T cell proliferation occurred in the peripheral lymphoid tissues including the spleen and LNs. Conclusions: These results suggest that a relatively low dose of TCDD impairs mucosal immunity in the gut and induces systemic sensitization by oral antigens.

Breakdown of mucosal immunity in gut by 2,3,7,8-tetraclorodibenzo-p-dioxin (TCDD)

<p><b>OBJECTIVES</b>Mucosal immunity plays a pivotal role for body defense against infection and allergy. The aim of this study was to clarify the effects of 2,3,7,8-tetraclorodibenzo-p-dioxin (TCDD) on mucosal immunity in the gut.</p><p><b>METHODS</b>Fecal IgA level and oral tolerance induction were examined in TCDD-treated mice. Flow cytometric and histological analyses were also performed.</p><p><b>RESULTS</b>Single oral administration of low dose 2,3,7,8-TCDD resulted in a marked decrease in IgA secretion in the gut without any effects on the cellular components of gut-associated lymphoid tissues (GALT) including Peyer's patches (PPs) and mesenteric lymph nodes (LNs). Decressed IgA secretion by TCDD was not observed in aryl hydrocarbon receptor (AhR)-deficient mice. Flow cytometric analysis revealed that IgA B cells in PPs and the mesenteric LNs remained unchanged in the TCDD-treated mice. An immunofluorescence study also demonstrated that a significant number of cytoplasmic IgA cells were present in the lamina propria of the gut in the TCDD-treated mice. Furthermore, oral tolerance induction by ovalbumin (OVA) was impaired in the TCDD-treated mice and OVA-specific T cell proliferation occurred in the peripheral lymphoid tissues including the spleen and LNs.</p><p><b>CONCLUSIONS</b>These results suggest that a relatively low dose of TCDD impairs mucosal immunity in the gut and induces systemic sensitization by oral antigens.</p>

Immune Regulatory Function of Dendritic Cells Expressing Indoleamine 2,3-Dioxygenase in Orally Tolerance to Type II Collagen-induced Animal Model

BACKGROUND: Immune regulatory dendritic cells (DCs) play an important role in maintaining self-tolerance. Recent evidences demonstrate that DCs expressing indoleamine 2,3-dioxygenase (IDO), which is involved in tryptophan catabolism, play an important role in immunoregulation and tolerance and induce T cell apoptosis. This study was devised to examine the role of IDO in the oral tolerance induction in collagen-induced arthritis (CIA) mouse model. METHODS: Beginning 2 weeks before immunization, CII was fed six times to DBA/1 mice and the effect on arthritis was assessed. In tolerized mice, CD11c+ DCs were isolated and stimulated with CII, IFN-gamma, and LPS with or without IDO inhibitor, 1-methyl-DL-tryptophan (1-MT) and IDO expression by CD11c+ DCs was analyzed using FACS and RT-PCR. The expression of IDO, MHC II, CD80, and CD86 by CD11c+ DCs were examined using confocal microscopy. Regulatory effect of CD11c+ DCs on Ag-specific T cell proliferative response to CII was examined by mixed lymphocyte reaction (MLR) with or without 1-MT. RESULTS: The proportion of IDO-expressing CD11c+ DCs was slightly higher in tolerized mice than in CIA mice and significantly increased after stimulation with CII, IFN-gamma, and LPS in an IDO- dependent manner. On confocal microscopic examination, the expression of IDO was higher and those of MHC II and CD86 were lower in CD11c+ DCs from tolerized mice compared to those from CIA mice. On MLR, CD11c+ DCs from tolerized mice inhibited T cell proliferative response to CII in an IDO-dependent manner. CONCLUSION: Enhanced IDO expression by CD11c+ DCs from tolerized mice may contribute to the regulation of proliferative response of CII-reactive T cells and could be involved in the induction of oral tolerance to CII.