Abstract
The treatment of auto-inflammatory disorders, such as inflammatory bowel disease (IBD), are often limited by unresponsiveness to single cytokine blockade, namely anti-TNF therapy. This is particularly important as treatment failure in IBD is associated with significant morbidity. The transcription factor T-bet is a critical regulator of intestinal homeostasis, is genetically linked to mucosal inflammation and controls the expression of multiple genes such as the proinflammatory cytokines IFN-γ and TNF-α. Inhibiting T-bet may therefore offer a more attractive prospect for treating IBD but remains challenging therapeutically. P-TEFb (CDK9-cyclin T), a transcriptional elongation factor downstream of T-bet, activates gene transcription by phosphorylating RNA polymerase II and its activity can be suppressed using CDK9 inhibitors.In this thesis, it was shown that CDK9 inhibition resulted in diminished serine 2 phosphorylation of RNA polymerase II with associated suppression of IFN-g and TNF-a production. Systemic CDK9 inhibition led to histological improvement of immune-mediated murine IBD, associated with targeted suppression of colonic CD4+ T cell-derived IFN-γ and IL-17A.
Transcriptomics data from human IBD colonic CD4+ T cells demonstrated that CDK9 inhibition preferentially repressed genes that were highly induced by P-TEFb, and these genes were often associated with T-bet enhancers. CDK9 inhibition resulted in significant repression of immune pathways implicated in numerous immune-mediated and inflammatory disorders.
CDK9 inhibition was effective at suppressing cytokine production by colonic lymphocytes from patients with anti-TNF resistant disease. Furthermore, transcripts repressed by CDK9 inhibition were highly expressed in anti-TNF resistant IBD raising expectations that CDK9 inhibitors may be efficacious in this difficult-to-treat cohort of patients. Collectively, these findings provide new insight into the therapeutic role of CDK9 inhibition for IBD, which has potential for rapid translation to the clinic.
| Date of Award | 1 May 2022 |
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| Original language | English |
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| Supervisor | Graham Lord (Supervisor) & Peter Irving (Supervisor) |