RESULTS Effect of TCDD Treatment on Body , Spleen , and Thymus Weight and EROD Activity in Liver Microsomes

Food allergy is an increasing health problem in Western countries. Previously, it has been shown that the intensity of food allergic reactions can be regulated by regulatory T (Treg) cells. In addition, it has been shown that activation of the aryl hydrocarbon receptor (AhR) regulates T-cell responses by induction of Treg cells. Therefore, we hypothesized that activation of the AhR pathway can suppress development of food allergic responses through the induction of Treg cells. This was investigated by using a mouse model for peanut allergy. C3H/HeOuJ mice (AhR) were sensitized to peanut by administering peanut extract (PE) by gavage in the presence of cholera toxin and were treated with the prototypical AhR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (0.6, 1.7, 5, and 15 mg/kg body weight) on days 3 and 11 orally. The functional role of CD4CD25Foxp3 Treg cells was investigated by depleting these cells with anti-CD25 mAb during sensitization to PE. TCDD treatment dose dependently suppressed sensitization to peanut (PE-specific IgE, IgG1, and IgG2a and PE-induced IL-5, IL-10, and IL-13, respectively). The percentage, but not the number, of CD4CD25Foxp3 Treg cells dose dependently increased by AhR activation in both spleen and mesenteric lymph nodes. Depletion of CD4CD25Foxp3 Treg cells markedly reversed the suppressive effect of TCDD on PEspecific antibody levels and PE-induced IL-5, IL-10, and IL-13 cytokine production. Present data demonstrate for the first time that activation of the AhR by TCDD suppressed the development of Th2-mediated food allergic responses. A functional shift within the CD4 cell population toward CD4CD25Foxp3 Treg cells appeared to underlie this effect. This suggests that the AhR pathway might provide potential therapeutic targets to treat food allergic diseases.

[1]  L. Boon,et al.  The role of intestinal dendritic cells subsets in the establishment of food allergy , 2011, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[2]  H. Weiner,et al.  An endogenous aryl hydrocarbon receptor ligand acts on dendritic cells and T cells to suppress experimental autoimmune encephalomyelitis , 2010, Proceedings of the National Academy of Sciences.

[3]  C. Esser,et al.  2,3,7,8-Tetrachlorodibenzo-p-dioxin impairs stable establishment of oral tolerance in mice. , 2010, Toxicological sciences : an official journal of the Society of Toxicology.

[4]  Kazuya Masuda,et al.  Aryl hydrocarbon receptor negatively regulates dendritic cell immunogenicity via a kynurenine-dependent mechanism , 2010, Proceedings of the National Academy of Sciences.

[5]  H. Weiner,et al.  Activation of the aryl hydrocarbon receptor induces human type 1 regulatory T cell–like and Foxp3+ regulatory T cells , 2010, Nature Immunology.

[6]  M. Veldhoen.  A toxin-sensitive receptor able to reduce immunopathology , 2010, Nature Immunology.

[7]  H. Weiner,et al.  The Aryl hydrocarbon Receptor (AhR) interacts with c-Maf to promote the differentiation of IL-27-induced regulatory type 1 (TR1) cells , 2010, Nature Immunology.

[8]  S. Navarro,et al.  Effects of TCDD on the fate of naive dendritic cells. , 2010, Toxicological sciences : an official journal of the Society of Toxicology.

[9]  L. Boon,et al.  Oligosaccharide-induced whey-specific CD25(+) regulatory T-cells are involved in the suppression of cow milk allergy in mice. , 2010, The Journal of nutrition.

[10]  Juan Ma,et al.  Suppression of experimental autoimmune uveoretinitis by inducing differentiation of regulatory T cells via activation of aryl hydrocarbon receptor. , 2010, Investigative ophthalmology & visual science.

[11]  Y. Setiady,et al.  In vivo depletion of CD4+FOXP3+ Treg cells by the PC61 anti‐CD25 monoclonal antibody is mediated by FcγRIII+ phagocytes , 2010, European journal of immunology.

[12]  R. Saavedra,et al.  Reduction of Foxp3+ Cells by Depletion with the PC61 mAb Induces Mortality in Resistant BALB/c Mice Infected with Toxoplasma gondii , 2009, Journal of biomedicine & biotechnology.

[13]  N. Kaminski,et al.  Simultaneous in vivo time course and dose response evaluation for TCDD-induced impairment of the LPS-stimulated primary IgM response. , 2009, Toxicological sciences : an official journal of the Society of Toxicology.

[14]  M. Shaker,et al.  An update on food allergy , 2009, Current opinion in pediatrics.

[15]  N. Kerkvliet.  AHR-mediated immunomodulation: the role of altered gene transcription. , 2009, Biochemical pharmacology.

[16]  F. Matsumura,et al.  Aryl hydrocarbon receptor signaling mediates expression of indoleamine 2,3-dioxygenase. , 2008, Biochemical and biophysical research communications.

[17]  E. Hauben,et al.  Activation of the aryl hydrocarbon receptor promotes allograft-specific tolerance through direct and dendritic cell-mediated effects on regulatory T cells. , 2008, Blood.

[18]  N. Kerkvliet,et al.  Functional Characterization and Gene Expression Analysis of CD4+CD25+ Regulatory T Cells Generated in Mice Treated with 2,3,7,8-Tetrachlorodibenzo-p-Dioxin1 , 2008, The Journal of Immunology.

[19]  H. Weiner,et al.  Control of Treg and TH17 cell differentiation by the aryl hydrocarbon receptor , 2008, Nature.

[20]  J. Buer,et al.  The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins , 2008, Nature.

[21]  H. Ochs,et al.  Immune dysregulation, polyendocrinopathy, enteropathy, X-linked: forkhead box protein 3 mutations and lack of regulatory T cells. , 2007, The Journal of allergy and clinical immunology.

[22]  T. Bushnell,et al.  Aryl Hydrocarbon Receptor Activation during Influenza Virus Infection Unveils a Novel Pathway of IFN-γ Production by Phagocytic Cells1 , 2007, The Journal of Immunology.

[23]  R. Pieters,et al.  CD4+CD25+ T cells regulate the intensity of hypersensitivity responses to peanut, but are not decisive in the induction of oral sensitization , 2007, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[24]  Masayuki Yamamoto,et al.  Effects of Aryl Hydrocarbon Receptor Signaling on the Modulation of Th1/Th2 Balance1 , 2005, The Journal of Immunology.

[25]  N. Kerkvliet,et al.  Cutting Edge: Activation of the Aryl Hydrocarbon Receptor by 2,3,7,8-Tetrachlorodibenzo-p-dioxin Generates a Population of CD4+CD25+ Cells with Characteristics of Regulatory T Cells1 , 2005, The Journal of Immunology.

[26]  W. Nacken,et al.  Role of the aryl hydrocarbon receptor in thymocyte emigration in vivo , 2005, European journal of immunology.

[27]  C. Tohyama,et al.  T cell-derived IL-5 production is a sensitive target of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). , 2005, Chemosphere.

[28]  M. Nagarkatti,et al.  Treatment of Mice with 2,3,7,8-Tetrachlorodibenzo-p-Dioxin Leads to Aryl Hydrocarbon Receptor-Dependent Nuclear Translocation of NF-κB and Expression of Fas Ligand in Thymic Stromal Cells and Consequent Apoptosis in T Cells1 , 2005, The Journal of Immunology.

[29]  R. Pieters,et al.  CTLA-4 Signaling Regulates the Intensity of Hypersensitivity Responses to Food Antigens, but is Not Decisive in the Induction of Sensitization , 2005, The Journal of Immunology.

[30]  N. Kerkvliet,et al.  Early consequences of 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure on the activation and survival of antigen-specific T cells. , 2004, Toxicological sciences : an official journal of the Society of Toxicology.

[31]  M. Denison,et al.  Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals. , 2003, Annual review of pharmacology and toxicology.

[32]  C. Tohyama,et al.  Suppressive effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the high-affinity antibody response in C57BL/6 mice. , 2003, Toxicological sciences : an official journal of the Society of Toxicology.

[33]  K. Mizuguchi,et al.  An orally active Th1/Th2 balance modulator, M50367, suppresses Th2 differentiation of naïve Th cell in vitro. , 2003, Cellular immunology.

[34]  N. Kerkvliet,et al.  Influence of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the antigen-presenting activity of dendritic cells. , 2003, Toxicological sciences : an official journal of the Society of Toxicology.

[35]  C. Tohyama,et al.  Mechanism of TCDD-induced suppression of antibody production: effect on T cell-derived cytokine production in the primary immune reaction of mice. , 2002, Toxicological sciences : an official journal of the Society of Toxicology.

[36]  J. Staessen,et al.  Immunologic biomarkers in relation to exposure markers of PCBs and dioxins in Flemish adolescents (Belgium). , 2002, Environmental health perspectives.

[37]  C. Tohyama,et al.  Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on T cell-derived cytokine production in ovalbumin (OVA)-immunized C57Bl/6 mice. , 2002, Toxicology.

[38]  C. Tohyama,et al.  Effect of a single oral dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin on immune function in male NC/Nga mice. , 2002, Toxicological sciences : an official journal of the Society of Toxicology.

[39]  N. Kerkvliet,et al.  Mechanism of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced decrease in anti-CD3-activated CD4(+) T cells: the roles of apoptosis, Fas, and TNF. , 2002, Toxicology.

[40]  R. Luebke,et al.  Suppression of allergic immune responses to house dust mite (HDM) in rats exposed to 2,3,7,8-TCDD. , 2001, Toxicological sciences : an official journal of the Society of Toxicology.

[41]  N. Kerkvliet,et al.  2,3,7,8-Tetrachlorodibenzo-p-dioxin affects the number and function of murine splenic dendritic cells and their expression of accessory molecules. , 2001, Toxicology and applied pharmacology.

[42]  N. Kerkvliet,et al.  The effects of TCDD on the activation of ovalbumin (OVA)-specific DO11.10 transgenic CD4(+) T cells in adoptively transferred mice. , 2000, Toxicological sciences : an official journal of the Society of Toxicology.

[43]  M. Nagarkatti,et al.  Characterization of phenotypic alterations induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin on thymocytes in vivo and its effect on apoptosis. , 1998, Toxicology and applied pharmacology.

[44]  Oliver H. Lowry,et al.  Protein measurement with the Folin phenol reagent. , 1951, The Journal of biological chemistry.

[45]  H. Sampson,et al.  Food allergy. , 2010, The Journal of allergy and clinical immunology.

[46]  H. Sampson,et al.  Food allergy: recent advances in pathophysiology and treatment. , 2009, Annual review of medicine.

[47]  A. Burks,et al.  New insights into diagnosis and treatment of peanut food allergy. , 2009, Frontiers in bioscience.

[48]  L D Burgoon,et al.  Comparative analysis of dioxin response elements in human, mouse and rat genomic sequences. , 2004, Nucleic acids research.

[49]  P. O'Byrne,et al.  Effect of interferon-gamma on allergic airway responses in interferon-gamma-deficient mice. , 2002, American journal of respiratory and critical care medicine.

[50]  M. van den Berg,et al.  The toxicokinetics and metabolism of polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) and their relevance for toxicity. , 1994, Critical reviews in toxicology.