Cyclin-dependent Kinase 9 as a Potential Target for Anti-TNF-resistant Inflammatory Bowel Disease.

Autor:	Omer OS; School of Immunology and Microbial Sciences, King's College London, London, UK; National Institute for Health Research Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust and King's College, London, UK., Hertweck A; UCL Cancer Institute and CRUK City of London Centre, University College London, London, UK., Roberts LB; School of Immunology and Microbial Sciences, King's College London, London, UK., Lo JW; School of Immunology and Microbial Sciences, King's College London, London, UK; Division of Digestive Diseases, Faculty of Medicine, Imperial College, London, UK., Clough JN; National Institute for Health Research Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust and King's College, London, UK., Jackson I; School of Immunology and Microbial Sciences, King's College London, London, UK., Pantazi ED; School of Immunology and Microbial Sciences, King's College London, London, UK; Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK., Irving PM; School of Immunology and Microbial Sciences, King's College London, London, UK; Inflammatory Bowel Disease Unit, Department of Gastroenterology, Guy's and St Thomas' NHS Foundation Trust, London, UK., MacDonald TT; Centre for Immunobiology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK., Pavlidis P; School of Immunology and Microbial Sciences, King's College London, London, UK., Jenner RG; UCL Cancer Institute and CRUK City of London Centre, University College London, London, UK. Electronic address: r.jenner@ucl.ac.uk., Lord GM; School of Immunology and Microbial Sciences, King's College London, London, UK; Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK. Electronic address: graham.lord@manchester.ac.uk.
Jazyk:	angličtina
Zdroj:	Cellular and molecular gastroenterology and hepatology [Cell Mol Gastroenterol Hepatol] 2022; Vol. 14 (3), pp. 625-641. Date of Electronic Publication: 2022 Jun 01.
DOI:	10.1016/j.jcmgh.2022.05.011
Abstrakt:	Background & Aims: Resistance to single cytokine blockade, namely anti-tumor necrosis factor (TNF) therapy, is a growing concern for patients with inflammatory bowel disease (IBD). The transcription factor T-bet is a critical regulator of intestinal homeostasis, is genetically linked to mucosal inflammation and controls the expression of multiples genes such as the pro-inflammatory cytokines interferon (IFN)-γ and TNF. Inhibiting T-bet may therefore offer a more attractive prospect for treating IBD but remains challenging to target therapeutically. In this study, we evaluate the effect of targeting the transactivation function of T-bet using inhibitors of P-TEFb (CDK9-cyclin T), a transcriptional elongation factor downstream of T-bet. Methods: Using an adaptive immune-mediated colitis model, human colonic lymphocytes from patients with IBD and multiple large clinical datasets, we investigate the effect of cyclin-dependent kinase 9 (CDK9) inhibitors on cytokine production and gene expression in colonic CD4 + T cells and link these genetic modules to clinical response in patients with IBD. Results: Systemic CDK9 inhibition led to histological improvement of immune-mediated colitis and was associated with targeted suppression of colonic CD4 + T cell-derived IFN-γ and IL-17A. In colonic lymphocytes from patients with IBD, CDK9 inhibition potently repressed genes responsible for pro-inflammatory signalling, and in particular genes regulated by T-bet. Remarkably, CDK9 inhibition targeted genes that were highly expressed in anti-TNF resistant IBD and that predicted non-response to anti-TNF therapy. Conclusion: Collectively, our findings reveal CDK9 as a potential target for anti-TNF-resistant IBD, which has the potential for rapid translation to the clinic. (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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