Supervisor View Full Details 2nd

• infectious disease and the immune system
• cancer/oncology

• Medicine

• Gastroenterology
• Haematology
• Immunology
• Oncology

My research focuses on the role of signalling molecules in immunology and inflammation and this has extended to inflammatory changes in oesophageal carcinoma. We have studied, at the molecular level, the mechanisms used by T lymphocytes to migrate and secrete cytokines, both important functions in the inflammatory response. During inflammation, blood vessels become more adhesive (mediated by cytokines) allowing lymphocytes to bind and migrate into tissue and carry out their function. Central to this work has been the study of a family of enzymes known as Protein Kinase C (PKC), which plays an important role in the regulation of these processes. As leukocyte migration from blood vessels and tumour cell metastasis share many common mechanisms, these studies have been extended to cancer cells where we have identified PKC as a target of tumourigenic bile acids.

In a translational sense, we have uncovered the molecular mechanisms that contribute to a number of human disease states. For example, how the hepatitis C virus can undermine the T cell immune response to maintain persistent infection and how environmental factors such as bile acids can contribute to oesophageal carcinogenesis. This is of key importance in the development of therapeutics for immune-related disorders and cancer.

T cell migration in Inflammatory Bowel Disease – mechanisms and therapeutic targets?

Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disorder of the gastrointestinal tract in genetically susceptible individuals. Ulcerative colitis and Crohn’s disease are the major subtypes of IBD. Epidemiological studies have estimated that IBD affects 396 per 100,000 individuals worldwide, while 320,000 people are affected by this disease in the UK and Ireland. Prevailing evidence indicates that IBD manifests as an inappropriate immune response to commensal microbes in the gastrointestinal tract, resulting in
(a) local activation of macrophages and the production of TNFα
(b) infiltration of inflammatory CD4+ T-cell subsets (Th1, Th2, Th17) and the production of inflammatory T-cell cytokines. This inappropriate inflammatory response leads to tissue damage in the gastrointestinal tract, resulting in relapsing episodes of severe abdominal pain, vomiting, diarrhoea and rectal bleeding.

We have set up an in vitro model of α4β7 integrin-positive T cell migration on the specific MADCAM-1 ligand. This model facilitates the characterization of the migratory mechanisms used by these cells, the investigation of modulators of α4β7-MADCAM-1 mediated adhesion and migration (e.g vedolizumab) and factors that interfere with this process. The aim of this project is to investigate the mechanism of α4β7 integrin-positive T cell adhesion to and migration on MAdCAM-1 in patients with IBD. It will also screen a library of small molecule inhibitors for their ability to block α4β7 integrin-stimulated migration and characterize potential drug targets.

Migration, as defined by cell polarity, 2-D live cell migration and 3-D (transmigration) is quantified by High Content Analysis (HCA). Cytokine/chemokine levels (stimulated, differentiated, α4β7+ cells) are measured using Evidence Investigator automated multiplex equipment.