Title | Activation of aryl hydrocarbon receptor by TCDD prevents diabetes in NOD mice and increases Foxp3+ T cells in pancreatic lymph nodes. |
Publication Type | Journal Article |
Year of Publication | 2009 |
Authors | Kerkvliet NI, Steppan LB, Vorachek W, Oda S, Farrer D, Wong CP, Pham D, Mourich DV |
Journal | Immunotherapy |
Volume | 1 |
Issue | 4 |
Pagination | 539-47 |
Date Published | 2009 Jul |
ISSN | 1750-7448 |
Keywords | Animals, CD4 Antigens, Cell Proliferation, Cells, Cultured, Diabetes Mellitus, Type 1, Forkhead Transcription Factors, Interleukin-2 Receptor alpha Subunit, Ligands, Lymph Nodes, Mice, Mice, Inbred NOD, Pancreas, Polychlorinated Dibenzodioxins, Receptors, Aryl Hydrocarbon, T-Lymphocytes, Regulatory |
Abstract | The ligand-activated transcription factor, aryl hydrocarbon receptor (AHR), is a novel inducer of adaptive Tregs. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), the most potent AHR ligand, induces adaptive CD4+CD25+ Tregs during an acute graft-versus-host (GvH) response and prevents the generation of allospecific cytotoxic T lymphocytes. TCDD also suppresses the induction of experimental autoimmune encephalitis in association with an expanded population of Foxp3+ Tregs. In this study, we show that chronic treatment of NOD mice with TCDD potently suppresses the development of autoimmune Type 1 diabetes in parallel with greatly reduced pancreatic islet insulitis and an expanded population of CD4+CD25+Foxp3+ cells in the pancreatic lymph nodes. When treatment with TCDD was terminated after 15 weeks (23 weeks of age), mice developed diabetes over the next 8 weeks in association with lower numbers of Tregs and decreased activation of AHR. Analysis of the expression levels of several genes associated with inflammation, T-cell activation and/or Treg function in pancreatic lymph node cells failed to reveal any differences associated with TCDD treatment. Taken together, the data suggest that AHR activation by TCDD-like ligands may represent a novel avenue for treatment of immune-mediated diseases. |
DOI | 10.2217/imt.09.24 |
Alternate Journal | Immunotherapy |
PubMed ID | 20174617 |
PubMed Central ID | PMC2823486 |
Grant List | P01-ES00040 / ES / NIEHS NIH HHS / United States P01 ES000040-436359 / ES / NIEHS NIH HHS / United States R01 ES016651 / ES / NIEHS NIH HHS / United States P30-ES00210 / ES / NIEHS NIH HHS / United States P30 ES000210-339009 / ES / NIEHS NIH HHS / United States P30 ES000210-329009 / ES / NIEHS NIH HHS / United States P01 ES000040 / ES / NIEHS NIH HHS / United States P30 ES000210 / ES / NIEHS NIH HHS / United States |