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The role of IL-17 in the pathogenesis of glomerulonephritis and ANCA-associated vasculitis

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Title: The role of IL-17 in the pathogenesis of glomerulonephritis and ANCA-associated vasculitis
Authors: Hamour, Sally
Item Type: Thesis or dissertation
Abstract: Immune-mediated glomerulonephritis and vasculitis accounts for over 10% of end-stage renal failure in the UK. The anti-neutrophil cytoplasm antibody(ANCA)-associated vasculitides (AAV) are a specific subset, characterised by the production of ANCA, and are idiopathic multi-system vasculitides affecting mainly small-calibre vessels and renal glomeruli. Extensive human and animal work by our group and others has attempted to dissect the mechanisms which underlie the pathogenesis of these conditions. Recently, an important development in our understanding of cellular immunity has been the identification of a subset of T-cells characterised by production of the pro-inflammatory cytokine interleukin-17 (IL-17). T-helper-17 (Th17) cells are implicated as critical mediators of autoimmune disease. I have attempted to characterise whether there is a role for Th17 cells in the pathogenesis of experimental glomerulonephritis and AAV. I have shown that IL-17-deficient mice are protected from nephrotoxic nephritis and have used cell transfer experiments to see whether disease susceptibility or protection can be conferred. Using bone marrow transplant experiments, I have also demonstrated (1) that haematopoietic cells are critical mediators of disease and (2) that local production of IL-17 has an unexpected protective role. In human work, using samples from patients with AAV, I have shown that IL-17 is over-expressed in serum from both acute and convalescent patients and is closely associated with levels of related cytokines such as IL-23. Patients with AAV have memory Th17 cells that respond to stimulation with ANCA autoantigens. IL-23 levels correlate with AAV disease activity. This work demonstrates a role for IL-17 and Th17 cells in experimental glomerulonephritis and AAV. IL-17 blockade is being trialled as a therapy for a number of autoimmune diseases. Improved understanding of the mechanisms of pathogenesis and protection by IL-17 in AAV and glomerulonephritis will enable better prediction of the effects of IL-17 blockade and bring benefits to patients.
Issue Date: Sep-2012
Date Awarded: Jan-2013
URI: http://hdl.handle.net/10044/1/14413
DOI: https://doi.org/10.25560/14413
Supervisor: Cook, Terence
Salama, Alan
Sponsor/Funder: Wellcome Trust (London, England)
Department: Medicine
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:Medicine PhD theses

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