TitleActivation of aryl hydrocarbon receptor by TCDD prevents diabetes in NOD mice and increases Foxp3+ T cells in pancreatic lymph nodes.
Publication TypeJournal Article
Year of Publication2009
AuthorsKerkvliet NI, Steppan LB, Vorachek W, Oda S, Farrer D, Wong CP, Pham D, Mourich DV
JournalImmunotherapy
Volume1
Issue4
Pagination539-47
Date Published2009 Jul
ISSN1750-7448
KeywordsAnimals, 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.

DOI10.2217/imt.09.24
Alternate JournalImmunotherapy
PubMed ID20174617
PubMed Central IDPMC2823486
Grant ListP01-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