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Title: The P2X7 receptor in immune cells
Author: Taylor, Simon Richard James
ISNI:       0000 0004 2679 5059
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2009
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The P2X7 receptor is a cation channel activated by high concentrations of ATP. Its stimulation is pro-inflammatory, with activation resulting in the release of cytokines (notably IL-1β), changes in plasma membrane lipid distribution, and cell death. A central role for P2X7 in IL-1β secretion via the NALP3 inflammasome has been confirmed in gene-deficient mice generated by GlaxoSmithKline (GSK) and Pfizer. It is abundantly expressed on cells of the immune system and may play a role in the pathogenesis of autoimmune disease, notable systemic lupus erythematosus (SLE). Indeed, P2X7 has become an important potential therapeutic target, and antagonists are currently in Phase II clinical trials for treatment of rheumatoid arthritis and chronic obstructive pulmonary disease. In this thesis, I describe my investigation into the role of the P2X7 receptor in immune function, examining in detail the responses of murine T cells, macrophages and dendritic cells to P2X7 stimulation. Investigation of T cell responses reveals a novel form of cell death in which cells initially shrink and then swell, before undergoing catastrophic lysis with release of cellular contents into the surrounding milieu, a process which I have termed aponecrosis as it bears features of both apoptosis and necrosis. In addition, I report a detailed characterisation of immune cells from the GSK P2X7-/- mouse. Functional and mRNA data demonstrate tissue-specific 'leakiness', such that P2X7 expression is ablated in P2X7-/- macrophages, but not in P2X7-/- T cells. This explains previous paradoxical experimental and immunohistochemical data achieved with P2X7-/- mice without the need to invoke the expression of an additional P2X7-like protein cross-reactive with P2X7 antibodies. Finally, I report the use of a mouse model of antibody-mediated glomerulonephritis to demonstrate that P2X7 plays a key pro-inflammatory role in immune-mediated injury and that this receptor is a possible therapeutic target in vivo.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available