PMID- 26573835
OWN - NLM
STAT- MEDLINE
DCOM- 20160518
LR  - 20170101
IS  - 1550-6606 (Electronic)
IS  - 0022-1767 (Linking)
VI  - 196
IP  - 1
DP  - 2016 Jan 1
TI  - Activation of the Aryl Hydrocarbon Receptor by 10-Cl-BBQ Prevents Insulitis and
      Effector T Cell Development Independently of Foxp3+ Regulatory T Cells in
      Nonobese Diabetic Mice.
PG  - 264-73
LID - 10.4049/jimmunol.1501789 [doi]
AB  - Aryl hydrocarbon receptor (AhR) activation by high-affinity ligands mediates
      immunosuppression in association with increased regulatory T cells (Tregs),
      making this transcription factor an attractive therapeutic target for autoimmune 
      diseases. We recently discovered
      10-chloro-7H-benzimidazo[2,1-a]benzo[de]iso-quinolin-7-one (10-Cl-BBQ), a
      nanomolar affinity AhR ligand with immunosuppressive activity and favorable
      pharmacologic properties. In this study, we tested the consequences of AhR
      activation in the NOD model. Oral 10-Cl-BBQ treatment prevented islet
      infiltration without clinical toxicity, whereas AhR-deficient NOD mice were not
      protected. Suppression of insulitis was associated with an increased frequency,
      but not total number, of Foxp3(+) Tregs in the pancreas and pancreatic lymph
      nodes. The requirement for Foxp3(+) cells in AhR-induced suppression of insulitis
      was tested using NOD.Foxp3(DTR) mice, which show extensive islet infiltration
      upon treatment with diphtheria toxin. AhR activation prevented the development of
      insulitis caused by the depletion of Foxp3(+) cells, demonstrating that Foxp3(+) 
      cells are not required for AhR-mediated suppression and furthermore that the AhR 
      pathway is able to compensate for the absence of Foxp3(+) Tregs, countering
      current dogma. Concurrently, the development of disease-associated
      CD4(+)Nrp1(+)Foxp3(-)RORgammat(+) cells was inhibited by AhR activation. Taken
      together, 10-Cl-BBQ is an effective, nontoxic AhR ligand for the intervention of 
      immune-mediated diseases that functions independently of Foxp3(+) Tregs to
      suppress pathogenic T cell development.
CI  - Copyright (c) 2015 by The American Association of Immunologists, Inc.
FAU - Ehrlich, Allison K
AU  - Ehrlich AK
AD  - Department of Environmental and Molecular Toxicology, Oregon State University,
      Corvallis, OR 97331; and.
FAU - Pennington, Jamie M
AU  - Pennington JM
AD  - Department of Environmental and Molecular Toxicology, Oregon State University,
      Corvallis, OR 97331; and.
FAU - Wang, Xisheng
AU  - Wang X
AD  - Department of Environmental and Molecular Toxicology, Oregon State University,
      Corvallis, OR 97331; and.
FAU - Rohlman, Diana
AU  - Rohlman D
AUID- ORCID: http://orcid.org/0000-0002-3982-0327
AD  - Department of Environmental and Molecular Toxicology, Oregon State University,
      Corvallis, OR 97331; and.
FAU - Punj, Sumit
AU  - Punj S
AD  - Department of Environmental and Molecular Toxicology, Oregon State University,
      Corvallis, OR 97331; and.
FAU - Lohr, Christiane V
AU  - Lohr CV
AUID- ORCID: http://orcid.org/0000-0003-3787-5583
AD  - College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331.
FAU - Newman, Matthew T
AU  - Newman MT
AD  - Department of Environmental and Molecular Toxicology, Oregon State University,
      Corvallis, OR 97331; and.
FAU - Kolluri, Siva K
AU  - Kolluri SK
AD  - Department of Environmental and Molecular Toxicology, Oregon State University,
      Corvallis, OR 97331; and.
FAU - Kerkvliet, Nancy I
AU  - Kerkvliet NI
AD  - Department of Environmental and Molecular Toxicology, Oregon State University,
      Corvallis, OR 97331; and nancy.kerkvliet@oregonstate.edu.
LA  - eng
GR  - R01 ES016651/ES/NIEHS NIH HHS/United States
GR  - 5R01ES016651/ES/NIEHS NIH HHS/United States
GR  - 5T32ES007060-35/ES/NIEHS NIH HHS/United States
GR  - P01 ES000040/ES/NIEHS NIH HHS/United States
GR  - T32 ES007060/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20151116
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0 (10-chloro-7H-benzimidazo(2,1-a)benzo(de)Isoquinolin-7-one)
RN  - 0 (Benzimidazoles)
RN  - 0 (Forkhead Transcription Factors)
RN  - 0 (Foxp3 protein, mouse)
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Isoquinolines)
RN  - 0 (Receptors, Aryl Hydrocarbon)
SB  - AIM
SB  - IM
MH  - Animals
MH  - Benzimidazoles/*administration & dosage/pharmacology
MH  - Diabetes Mellitus, Type 1/*prevention & control
MH  - Enzyme Activation
MH  - Forkhead Transcription Factors/metabolism
MH  - Immunosuppressive Agents/*administration & dosage/pharmacology
MH  - Inflammation/*prevention & control
MH  - Islets of Langerhans/*drug effects/immunology
MH  - Isoquinolines/*administration & dosage/pharmacology
MH  - Lymph Nodes/cytology/immunology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Inbred NOD
MH  - Receptors, Aryl Hydrocarbon/*agonists
MH  - Th1 Cells/*immunology
MH  - Th17 Cells/*immunology
PMC - PMC4684970
MID - NIHMS731884
EDAT- 2015/11/18 06:00
MHDA- 2016/05/19 06:00
CRDT- 2015/11/18 06:00
PHST- 2015/08/06 00:00 [received]
PHST- 2015/10/15 00:00 [accepted]
PHST- 2015/11/18 06:00 [entrez]
PHST- 2015/11/18 06:00 [pubmed]
PHST- 2016/05/19 06:00 [medline]
AID - jimmunol.1501789 [pii]
AID - 10.4049/jimmunol.1501789 [doi]
PST - ppublish
SO  - J Immunol. 2016 Jan 1;196(1):264-73. doi: 10.4049/jimmunol.1501789. Epub 2015 Nov
      16.