title: Benzimidazoisoquinolines: a new class of rapidly metabolized aryl hydrocarbon receptor (AhR) ligands that induce AhR-dependent Tregs and prevent murine graft-versus-host disease.
abstract: 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.
authors.affiliation: Department of Environmental & Molecular Toxicology, Oregon State University, Corvallis, Oregon, United States of America.
authors.forename: Sumit
authors.initials: S
authors.lastname: Punj
authors.affiliation: Department of Environmental & Molecular Toxicology, Oregon State University, Corvallis, Oregon, United States of America.
authors.forename: Prasad
authors.initials: P
authors.lastname: Kopparapu
authors.affiliation: Department of Environmental & Molecular Toxicology, Oregon State University, Corvallis, Oregon, United States of America.
authors.forename: Hyo Sang
authors.initials: HS
authors.lastname: Jang
authors.affiliation: Department of Environmental & Molecular Toxicology, Oregon State University, Corvallis, Oregon, United States of America.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Phillips
authors.affiliation: Department of Environmental & Molecular Toxicology, Oregon State University, Corvallis, Oregon, United States of America.
authors.forename: Jamie
authors.initials: J
authors.lastname: Pennington
authors.affiliation: Department of Environmental & Molecular Toxicology, Oregon State University, Corvallis, Oregon, United States of America.
authors.forename: Diana
authors.initials: D
authors.lastname: Rohlman
authors.affiliation: Department of Environmental & Molecular Toxicology, Oregon State University, Corvallis, Oregon, United States of America.
authors.forename: Edmond
authors.initials: E
authors.lastname: O'Donnell
authors.affiliation: Department of Environmental & Molecular Toxicology, Oregon State University, Corvallis, Oregon, United States of America.
authors.forename: Patrick L
authors.initials: PL
authors.lastname: Iversen
authors.affiliation: Department of Environmental & Molecular Toxicology, Oregon State University, Corvallis, Oregon, United States of America ; Environmental Health Sciences Center, Oregon State University, Corvallis, Oregon, United States of America.
authors.forename: Siva Kumar
authors.initials: SK
authors.lastname: Kolluri
authors.affiliation: Department of Environmental & Molecular Toxicology, Oregon State University, Corvallis, Oregon, United States of America ; Environmental Health Sciences Center, Oregon State University, Corvallis, Oregon, United States of America.
authors.forename: Nancy I
authors.initials: NI
authors.lastname: Kerkvliet
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control*; D007167:Immunotherapy; D007546:Isoquinolines / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology*; D007700:Kinetics; D008024:Ligands; D051379:Mice; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D013329:Structure-Activity Relationship; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology*
chemical_list: C000593972:10-chloro-7H-benzimidazo(2,1-a)benzo(de)Isoquinolin-7-one; D001562:Benzimidazoles; D007546:Isoquinolines; D008024:Ligands; D018336:Receptors, Aryl Hydrocarbon