Ian Dransfield's research has been directed towards understanding the role of clearance of inflammatory cells which have undergone programmed cell death (apoptosis) in the termination of inflammatory responses.
Nicole Barth - Optima PhD student (co-supervised with Marc Vendrell/Sarah Walmsley)
Investigation of mechanisms of phagocytosis of apoptotic cells by macrophages.
The recruitment of white blood cells (leukocytes) is an important part of inflammation, the body's defence against injury or infection. Once the infectious agent has been eliminated, an important part of the repair process is that these recruited leukocytes are cleared away from the site of injury/infection. The recruited leukocytes "die" (an event termed apoptosis) and are removed by other cells (called phagocytes) that act as a "garbage disposal system". It is now clear that when this process of dead cell removal is defective, it can lead to development of inflammatory diseases in many different organs, including the lung, liver, and the brain. We have shown that macrophage capacity for removal of dying cells can be increased by triggering specific receptors on the macrophage surface (eg CD44) and by powerful anti-inflammatory compounds (glucocorticoids). Although synthetic glucocorticoids are widely used to treat inflammatory diseases, there are many severe side effects associated with long term use of these agents, including weakening of bones, high blood pressure, muscle wasting, delayed wound healing and increased risk of infections. In addition, some patients do not respond very well to these anti-inflammatory drugs, although it is not known why. We aim to define alternative approaches that would potentially bypass the undesirable consequences of glucocorticoid therapy. We have shown that Mer is required for the increased efficiency of clearance of dying leukocytes induced by glucocorticoids, allowing the specific recognition of the dying leukocytes by the phagocytes and controlling the removal process. Our data provide new opportunities to understand the anti-inflammatory actions of glucocorticoids and identify new ways to control the clearance of dying cells for therapeutic gain in inflammatory disease. Importantly, we hope to identify ways to promote resolution of inflammation which will avoid the detrimental effects of glucocorticoids themselves.
We have analysed the molecular changes on the surface of white blood cells as they undergo cell death and shown that there is specific loss of membrane receptors (eg CD16 and L-selectin). Together with loss of adhesive function, these changes may be important in the removal of dying neutrophils following an inflammatory response. We have found that a receptor for aggregated antibodies (FcgammaRII) becomes switched on during apoptosis. One consequence of this is that dying neutrophils may bind antibody and, as a consequence, be recognised by macrophages in a different way. This may be particularly important in diseases like rheumatoid arthritis and systemic lupus erythematosus, where antibody aggregates are present and have shown that molecules that mediate leucocyte adhesion act to control the extent of cellular activation and thus the potential for tissue destruction.
Our previous work showed that binding of white blood cells to platelets was increased in patients with evidence of injury to heart tissue. We have therefore investigated the molecules that allow binding to occur and whether there are potentially damaging consequences of this binding in terms of white blood cell function. Increased platelet binding switches on the destructive potential of the white blood cells and we have recently identified that, in addition to the molecules that are involved in platelet binding, there are also soluble factors required to trigger the acquisition of this dangerous behaviour of the white blood cells.
During inflammation, white blood cells (leucocytes) are rapidly recruited from the blood to inflamed sites to destroy infectious micro-organisms and to begin the process of tissue repair. However, these normally protective responses appear to be perturbed in inflammatory diseases, resulting in tissue destruction and persistence of inflammation. Our research has been directed towards understanding the mechanisms by which leucocyte function can be "fine-tuned", which we hope will allow development of new strategies for control of tissue damage without compromising important anti-microbial defence mechanisms.