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Benzimidazoisoquinolines: a new class of rapidly metabolized aryl hydrocarbon receptor (AhR) ligands that induce AhR-dependent Tregs and prevent murine graft-versus-host disease Public Deposited

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https://ir.library.oregonstate.edu/concern/articles/3x816n34q

Please view the version of record at  http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0088726 Copyright: © 2014 Punj et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. PLoS ONE 9(2): e88726. doi:10.1371/journal.pone.0088726

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  • The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that plays multiple roles in regulation of immune and inflammatory responses. The ability of certain AhR ligands to induce regulatory T cells (Tregs) has generated interest in developing AhR ligands for therapeutic treatment of immune-mediated diseases. To this end, we designed a screen for novel Treg-inducing compounds based on our understanding of the mechanisms of Treg induction by the well-characterized immunosuppressive AhR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). We screened a ChemBridge small molecule library and identified 10-chloro-7H-benzimidazo[2,1-a]benzo[de]​Iso-quinolin-7-one(10-Cl-BBQ) as a potent AhR ligand that was rapidly metabolized and not cytotoxic to proliferating T cells. Like TCDD,10-Cl-BBQ altered donor CD4+ T cell differentiation during the early stages of a graft versus host (GVH) response resulting in expression of high levels of CD25, CTLA-4 and ICOS, as well as several genes associated with Treg function. The Treg phenotype required AhR expression in the donor CD4+ T cells. Foxp3 was not expressed in the AhR-induced Tregs implicating AhR as an independent transcription factor for Treg induction. Structure-activity studies showed that unsubstituted BBQ as well as 4, 11-dichloro-BBQ were capable of inducing AhR-Tregs. Other substitutions reduced activation of AhR. Daily treatment with 10-Cl-BBQ during the GVH response prevented development of GVH disease in an AhR-dependent manner with no overt toxicity. Together, our data provide strong support for development of select BBQs that activate the AhR to induce Tregs for treatment of immune-mediated diseases.
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  • Punj S, Kopparapu P, Jang HS, Phillips JL, Pennington J, et al. (2014) Benzimidazoisoquinolines: A New Class of Rapidly Metabolized Aryl Hydrocarbon Receptor (AhR) Ligands that Induce AhR-Dependent Tregs and Prevent Murine Graft-Versus-Host Disease. PLoS ONE 9(2): e88726. doi:10.1371/journal.pone.0088726
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  • 9
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  • 2
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  • This research was funded by NIH grant 5RO1ES016651 to NIK and SKK. Technical support in flow cytometry and mass spectroscopy was provided by the Environmental Health Sciences Core Center at OSU, funded by NIEHS Center grant P01ES00210.
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  • description.provenance : Made available in DSpace on 2014-02-27T18:50:32Z (GMT). No. of bitstreams: 2 license_rdf: 1370 bytes, checksum: cd1af5ab51bcc7a5280cf305303530e9 (MD5) KirkvleitNancyEnvMolToxicologyBenzimidazoisoquinolines.pdf: 1711238 bytes, checksum: e2d2b28d32d4dbcb8a8dbb4ea63ac56c (MD5) Previous issue date: 2014-02-19
  • description.provenance : Approved for entry into archive by Sue Kunda(sue.kunda@oregonstate.edu) on 2014-02-27T18:50:32Z (GMT) No. of bitstreams: 2 license_rdf: 1370 bytes, checksum: cd1af5ab51bcc7a5280cf305303530e9 (MD5) KirkvleitNancyEnvMolToxicologyBenzimidazoisoquinolines.pdf: 1711238 bytes, checksum: e2d2b28d32d4dbcb8a8dbb4ea63ac56c (MD5)
  • description.provenance : Submitted by Sue Kunda (sue.kunda@oregonstate.edu) on 2014-02-27T18:50:14Z No. of bitstreams: 2 license_rdf: 1370 bytes, checksum: cd1af5ab51bcc7a5280cf305303530e9 (MD5) KirkvleitNancyEnvMolToxicologyBenzimidazoisoquinolines.pdf: 1711238 bytes, checksum: e2d2b28d32d4dbcb8a8dbb4ea63ac56c (MD5)

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