Investigators and Projects
Inflammatory processes are the body’s defence against local damage and disease. Inflammation involves the influx into organs of immune cells (white blood cells) from the blood. These cells deal with microbes and repair tissue damage. Two main sub-types of immune cells are T cells and macrophages. T cells are designed to recognise the molecular signatures of particular proteins, such as those from bacteria, in order to activate an immune response. Macrophages eat other cells and are able to pull apart their proteins in order to present them to T cells. However, if T cells respond to one’s own proteins, inappropriate inflammation can result, causing damage to healthy organs. This is known as autoimmune disease. Such inflammation is particularly harmful in the eye, since tissue damage and the pressure caused by the numbers of immune cells entering, disrupts the delicate organisation of the eye that is required for sight.
Macrophages interact with T cells in order to bring about T cell activation in target organs, and are themselves activated by inflammatory messenger molecules (cytokines) produced by the T cells. Macrophages produce toxic chemicals, such as nitric oxide, that can kill surrounding cells. Our research and that of others has shown that macrophages stimulated by T cells need to produce a second inflammatory cytokine (TNFα), which is needed as a signal to tell the macrophages to produce nitric oxide. Modulating this is now being used in the clinic to treat autoimmune inflammatory eye disease.
Many other signals (both secreted chemicals and cell-cell surface interactions) also control the outcome of interaction between macrophages and T cells. These may be important targets for medical therapy and so research in this project aims to reveal the details of this inflammatory process, with the long term goal of identifying novel, more effective and more specific targets to treat blinding diseases caused by autoimmunity.
Khera, T. K., Copland, D. A., Boldison, J., Lait, P. J. P., Szymkowski, D. E., Dick, A. D. & Nicholson, L. B. (2012)TNF-mediated macrophage activation in the target organ is critical for clinical manifestation of uveitis. Clinical & Experimental Immunology 168: 165-177.
Fordham, J.B., Hua, J., Moorwood, S.R., Schewitz-Bowers, L.P., Copland, D.A., Dick, A.D. & Nicholson, L.B. (2012) Environmental conditioning in the control of macrophage thrombospondin-1 production
Scientific Reports 2, 512; DOI:10.1038/srep00512
Raveney, B. J. E., Copland, D. A., Calder, C.J., Dick, A. D. and Nicholson, L.
B. (2010) TNFR1 signalling is a critical checkpoint for developing macrophages
that control T-cell proliferation
Immunology 131: 340-349.
DOI: 10.1111/j.1365-2567.2010.03305.x
Raveney, B. J. E., Copland, D. A., Dick, A. D., and Nicholson, L. B. (2009) TNFR1-Dependent Regulation of Myeloid Cell Function in Experimental Autoimmune Uveoretinitis J. Immunol 183: 2321-2329
Nicholson, L. B., Raveney, B. J. E., and Munder, M. (2009) Monocyte dependent
regulation of autoimmune inflammation.
Current Molecular Medicine 9: 23-29