The role of P2X7 in Autoimmune Vasculitis

Lead Research Organisation: Imperial College London
Department Name: Dept of Medicine

Abstract

Vasculitis (inflammation of the blood vessels) is an inflammatory disease which can damage different organs of the body. One of the more common types of vasculitis involves the presence of an autoantibody (ANCA). ANCA associated vasculitis (AAV) is a systemic disease that affects multiple organ systems including a rapidly progressive injury in the kidney and life threatening lung haemorrhage. There have been developments in treatment for this condition, but they remain non-specific and are associated with significant side effects.
The P2X7R is a receptor on cells which is not present in healthy glomeruli (filtering units of the kidney) but has been shown to have a role in inflammation and scarring of the kidneys in both human disease and animal models. I aim to study this receptor both in patients with vasculitis and also in an experimental model of vasculitis in rats, affecting both the kidney and the lung, which resembles ANCA associated vasculitis in humans. I shall also use blood and kidney tissue from patients with AAV to study the levels of P2X7R in both kidney tissue and white blood cells. In particular I will examine the role of P2X7R in production of autoantibodies and the pathways by which it causes inflammation. We shall investigate the functional importance of P2X7R using a pharmacological inhibitor and then validate the results by using rats with deletion of the gene for P2X7R. The effect of these experiments on disease activity will be assessed.
Our results will further understanding of the role of P2X7R in kidney inflammation, which may lead to development of new treatments for patients with vasculitis.

Technical Summary

Antinuclear cytoplasm antibody (ANCA) associated vasculitis (AAV) is an important cause of morbidity and mortality causing multisystem organ damage, including glomerulonephritis (GN) with subsequent progression to renal failure, and life-threatening lung haemorrhage. Better-targeted are needed. The P2X7 receptor (P2X7R) is an ATP-sensitive cell surface receptor with multiple roles, including inflammatory cytokine production and release, apoptosis and antigen presentation. P2X7R mediates renal injury in immune complex mediated GN. However, antibody deposition is not a prominent feature of pauci-immune GN in AAV, the role of P2X7R as a novel therapeutic target in AAV remains to be investigated. We hypothesise that P2X7R is critical in the production of ANCA and leucocyte activation leading to glomerular and lung injury.
We aim to investigate a role for P2X7R in patients with AAV and also in a model of myeloperoxidase (MPO) induce experimental autoimmune vasculitis (EAV) in Wistar-Kyoto (WKY) rats.
The objectives of the project are to investigate:
1. P2X7R expression in renal biopsies and peripheral blood leucocytes in patients with AAV, and whether P2X7R synergises with ANCA in the activation of macrophages and neutrophils in vitro.
2. The role of P2X7R in the EAV model. I will (i) detect P2X7R and its downstream pathways and their cellular localization; (ii) use a P2X7R antagonist to prevent or treat disease and measure autoantibody production, inflammasome activation, cytokine production, and severity of renal and lung injury; (iii) the effect of P2X7R genetic deletion in WKY rats will be analysed as in (ii); (iv) use bone marrow transplantation between wildtype and knockout rats to determine if immune or renal cells are more important in mediating disease.
3. The role of P2X7R in antigen presentation and leucocyte responses to ANCA in vitro using dendritic cells, T cells, macrophages and neutrophils from WKY rats using P2X7R knockout and antagonist.

Planned Impact

The results from this research project have the potential to lead to a successful clinical trial using P2X7R antagonists in the treatment of autoimmune vasculitis and glomerulonephritis. Current treatment protocols are non-specific and associated with significant morbidity themselves. A more effective treatment for vasculitis has the potential to benefit patients with vasculitis and glomerulonephritis. These results would also be applicable to patients with other multisystem and inflammatory conditions. Patients would be subject to less drug toxicity with reduced complications.

The NHS and other health care organisations could also benefit from this research. With the development of a more effective, selective treatment for vasculitis there would be decreased costs associated with hospitalization for treatment complications and with fewer patients progressing to end stage renal failure decreased costs from transplantation and dialysis.

Further evidence for the use of P2X7R antagonists in treatment of inflammatory conditions will be of use to colleagues working in the pharmaceutical industry and would stimulate further work into new antagonists and clinical trials. Charities and kidney patient groups have the potential to benefit from this research. Glomerulonephritis and vasculitis are not well known about by the general public. A successful clinical trial would raise the profile of research into vasculitis and other forms of renal disease.

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