Research Interests

Little is known of how the immune system functions in epithelial organs. Our aim is to elucidate the functional and molecular basis for interactions between the immunocytes and normal epithelial cells, and how these interactions may be modified during inflammation and wound-healing and following neoplastic transformation. Our strategy is to use cell and molecular biology and immunology approaches to study the phenomena in human in vitro model systems.
Much of our work concentrates on human epithelial cells of the urinary bladder, which provide an excellent model system of normal epithelial growth, differentiation and wound-healing responses. Methods for the reliable propagation of normal urothelial cells were developed in conjunction with Jenny Southgate (Jack Birch Unit, University of York), and we now have “paramalignant” cells (normal cells with disabled gene function) as well as a large panel of human tumour-derived cell-lines of varying degrees of differentiation and anaplasty.

The TNF Superfamily and the Control of Epithelial Cell Fate
In the immune system, members of the TNF/TNFR superfamilies are involved in diverse regulatory activities, including cell activation, differerentiation and induction of apoptosis. Little is known of their role in epithelial cell systems. Although Fas ligation induces apoptosis in immunocytes, normal human bladder epithelial cells and many bladder carcinoma cells are relatively resistant to Fas-mediated killing. In collaboration with John Gordon (Birmingham), we have shown that carcinoma cells can be killed very efficiently by CD40 ligation, but only if the ligand is cell surface-presented. By contrast, CD40 can transmit a mitogenic signal, rather than death-inducing signal in normal cells. We are currently unravelling the mechanism(s) involved in the control of urothelial cell fate by CD40.
Other members of the TNF superfamily currently under investigation are TRAIL and the Lymphotoxin system.

Modulation of T cell Activation by Epithelial Cells
Although it is widely assumed that epithelial cells are immunologically “silent”, or can even act as antigen-presenting cells, the data in this respect are scant. We have previously shown that human biliary epithelial cells suppress mitogen-driven T cell activation in the presence of accessory cells. We have now shown a similar phenomenon with human urothelial cells, with impaired activation to mitogen or recall antigen. Furthermore, normal epithelial cells are not allostimulatory alone, but appear to modulate accessory function, leading to the generation of hyporesponsive T cells akin to classical anergy, which can be overcome with exogenous IL-2.
Current work is aimed at understanding the mechanism(s) involved and the role of accessory molecules of the recently-discovered B7H family.