Benzimidazoisoquinolines: a new class of rapidly metabolized aryl hydrocarbon receptor (AhR) ligands that induce AhR-dependent Tregs and prevent murine graft-versus-host disease
| Autor: | Siva Kumar Kolluri, Hyo Sang Jang, Jamie M. Pennington, Sumit Punj, Patrick L. Iversen, Diana Rohlman, Jessica Lynne Phillips, Prasad Rao Kopparapu, Edmond F. O’Donnell, Nancy I. Kerkvliet |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
medicine.medical_treatment
Graft vs Host Disease lcsh:Medicine Ligands T-Lymphocytes Regulatory Biochemistry Mice 0302 clinical medicine Molecular Cell Biology Cytotoxic T cell Membrane Receptor Signaling IL-2 receptor Biomacromolecule-Ligand Interactions Receptor lcsh:Science 0303 health sciences Multidisciplinary biology Clinical Pharmacology FOXP3 Signaling in Selected Disciplines respiratory system 3. Good health 030220 oncology & carcinogenesis Medicine Immunotherapy Immunologic Receptor Signaling Research Article Signal Transduction Drugs and Devices Immunology chemical and pharmacologic phenomena Immunopathology Immunological Signaling Structure-Activity Relationship 03 medical and health sciences Immune system medicine Animals Biology Transcription factor 030304 developmental biology Transplantation lcsh:R Immunologic Subspecialties Isoquinolines Aryl hydrocarbon receptor Kinetics Receptors Aryl Hydrocarbon biology.protein Cancer research Benzimidazoles Clinical Immunology lcsh:Q |
| Zdroj: | PLoS ONE, Vol 9, Iss 2, p e88726 (2014) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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