The research in the Unit encompasses: autoimmunity, neuro-immune interactions, effects of nitric oxide (NO) and reactive oxygen species on biomolecules and cells, the role of neuropeptides in pain and inflammation, and gene therapy. Cell biologists, immunologists, biochemists and molecular biologists work together in order to develop genetic methods for therapy of chronic diseases. As new targets are defined during investigations using clinical material and experimental animal models of human diseases, so are methods of gene delivery and therapeutic applications sought. Defining the inter-cellular mediators that play a role in pathogenesis such as cytokines, metalloproteinases, neuropeptides, reactive oxygen species (ROS), and their natural antagonists such as soluble receptors, tissue inhibitors of metalloproteinases (TIMPs), and scavenging enzymes such as superoxide dismutase and catalase facilitates the development of strategies using their genes as potential therapeutic agents.

Modulation of the immune response has been the main target of our efforts.  The feasibility of gene therapy is being studied in animal models of arthritis, multiple sclerosis and cancer, using retroviruses and plasmids as delivery vectors expressing cytokines and cytokine inhibitors.  The use of other viral vectors with different capabilities is also being considered. In autoimmune disease models we have beneficially used anti-inflammatory cytokines such as transforming growth factor beta 1 (TGFb1), interferon b (IFN b) and interleukin 4  (IL-4). Also, we have inhibited pro-inflammatory cytokines, such as tumour necrosis factor (TNF), by delivering a genetically engineered, dimerized form of its soluble receptor, which proved to be a very potent treatment in both arthritis and multiple sclerosis model systems. Other mediators that we have targeted include the complement cascade using soluble complement receptor 1 (CR1/CD35) and a pro-apoptotic mammalian lectin named galectin-1.

In addition to defining the therapeutic gene(s) to use, the delivery of these agents to the specific site of inflammation or affected tissue is being investigated. We have provided evidence that the pathogenic white blood cell (T lymphocyte) that is capable of transferring the autoimmune disease to a healthy animal is an appropriate carrier of therapeutic genes. These T cells can migrate across endothelial barriers from the blood to the organs, recognise with exquisite specificity tissue structures, and proliferate in situ. We have harnessed these properties for therapeutic purposes with important biological/therapeutic effects.  For example, an arthritogenic T cell engineered to produce TGFb1, not only inhibits arthritis by stopping the autoimmune reaction but also protects the joint by inhibiting collagenase activity via the induction of TIMP-1 and by its anabolic effects on cartilage, inducing collagen and proteoglycan synthesis.

Currently, we are re-targeting T lymphocytes to specific tissues by engineering them with retroviruses expressing chimeric receptors comprised of an extracellular domain made of an antibody binding site and a cytoplasmic signalling domain from the T cell receptor signaling complex.  This engineered chimeric receptor enables the T cells to respond to specific "tissue antigen" by proliferating and secreting cytokines. 

Work by members of the Unit has helped define the hypoxic conditions in the joint of rheumatoid arthritis patients. This pathological state could be used to up-regulate in vivo therapeutic genes. Thus, hypoxia-regulated vectors are being designed that will work within this particular environment.