Mechanisms of glucocorticoid resistance in inflammatory diseases of the gut and liver

Glucocorticoids (GCs) are widely used to treat inflammatory diseases of the gut and liver. However, they are ineffective in up to a third of patients. In ulcerative colitis (UC) such GC resistant individuals require a colectomy, while patients with severe alcoholic hepatitis (AH) develop fatal progressive liver failure. Early stratification of these high-risk patients is critical to improve our understanding of the mechanisms of GC resistance and also for the development of better therapies. The work presented in this thesis aimed to extend the application of a candidate biomarker of GC resistant disease from UC to AH. Based on this, differential lymphocyte responses to GCs were then interrogated, and the effect of interleukin-2 on GC responsiveness assessed. An evaluation of the role of different T helper (Th) cell subsets in driving the GC resistant phenotype was then conducted, followed by an investigation of the role of monocytes in shaping these T cell responses to GCs. These studies have confirmed that the in vitro effect of GCs on lymphocyte proliferation corresponds with clinical outcome in AH as well as UC, highlighting the role of T cell responses. Blockade of IL-2 improved GC sensitivity in vitro and investigation of intracellular signalling pathways demonstrated that there was impaired GC regulation of the pro-inflammatory transcription factor NFKB in GC resistant cells. NFKB can induce Th17 cell differentiation and IL-17 expression was found to be refractory to GC suppression in CD4+ T cells. Toll-like receptors (TLRs) were then shown to influence monocyte-mediated CD4+ T cell differentiation in both man (in vitro) and mouse (in vivo). Monocyte subsets were critical in determining this T cell fate, and innate immune responses are therefore a key potential driver of the GC resistant phenotype. This work has led to the development of a protocol for a Phase II clinical trial of IL-2 blockade in GC resistant AH and also further mechanistic studies to evaluate the role of monocytes in GC resistant diseases.