Investigating and targeting monocyte-macrophage cellular effectors in ANCA associated vasculitis (360G-Wellcome-090048_B_09_Z)

The pathophysiology of ANCA associated vasculitis remains incompletely understood but with the development of novel animal models we have the tools to investigate the key processes initiating and propogating disease. Monocytes/macrophages are frequently found in affected organs. However, the precise role they play and the effect their differental states of activation play in disease are still unclear. This proposal seeks to investigate the role of monocyte/macrophage activation and polarisation in ANCA associated disease, using our autoimmune immunised rat model and patient material. Our hypothesis is that the state of macrophage activation dictates disease phenotype and outcome. As such targeting the key processes in macrophage activation should provide a novel rational therapeutic approach. We will make use of the model we have developed to investigate the genetic predisposition to disease using a series of congenic animals we have generated, the role of signalling pathways in vivo a nd the macrophage phenotype. These results will be compared with patients and the correlation between macrophage activation and disease phenotype will be made.