Inflammatory bowel diseases
Ulcerative Colitis (UC) and Crohn’s disease (CD) are the two main forms of inflammatory bowel disease (IBD) and are likely to result from distinct mechanisms. Interplay between the gut microbiota and the immune system in genetically susceptible individuals plays an essential role in disease development and both Th1 and Th17 T cell responses have been shown to play an integral part in driving pathology. First-line treatments for IBD focus on anti-inflammatories and there remains an unmet need to target pathological immune responses, both innate and adaptive, in a specific manner. We use a DSS-colitis inflammatory model to test novel therapeutics and examine their effects on the frequency and phenotype of both infiltrating leukocytes and circulating T cells, and to characterise the composition of intraepithelial lymphocytes (IEL) and gut lamina propria (LP) immune subsets. The relative proportions of Th17, Th1 and Treg were determined for each tissue. To complement this, we have developed a range of human primary T cell in vitro assays. Naïve CD4+ T cells from healthy donor blood samples were differentiated into helper T cell subsets or iTreg under polarising conditions. The ability of novel compounds to inhibit Th1/17 differentiation or to drive iTreg generation was then determined. Treg suppression assays were also performed. These models provide a compound screening platform which delivers synergistic information on efficacy and mode of action whilst also enabling biomarker discovery.