The Role of Angiopoietins 1 and 2 in ANCA Associated Vasculitis

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Vasculitis encompasses a group of disorders characterised by inflammation and destruction of blood vessels. Anti-neutrophil cytoplasmic antibody (ANCA) vasculitis is a subtype of vasculitis in which white blood cells are activated by proteins in the blood that normally fight infection. These white blood cells then attack blood vessels throughout the body including the kidneys. The outcome of untreated vasculitis is very poor and in many patients the kidneys are severely damaged so that dialysis is needed. At present the mainstay of treatment in vasculitis is substantial suppression of the immune system, which in itself is associated with significant morbidity and mortality. A better and clearer understanding of the mechanisms that underlie the cause of vasculitis at a cellular level will help refine therapy.Our objective is to explore the role of growth factors called angiopoietins 1 and 2. The endothelium (internal cell surface of blood vessels) is thought to drive the inflammation which ultimately leads to its own destruction and leads to the complications associated with vasculitis. Angiopoietins have a role in the maintenance of the endothelium integrity and we predict that they have a crucial role in the inflammatory cycle associated with vasculitis. An understanding of the endothelium and immune system interaction will help in the discovery of more focused treatment options and improve the prognosis of vasculitis.Angiopoietins 1 and 2 are made by different blood vessel constituents. The role of angiopoietins have been explored in development of organs and in tumour biology, however its role in active blood vessel inflammation in vasculitis has not been explored. Published data show that these growth factors do influence the cells of the immune system, implicating them in inflammation. Mice that do not make angiopoietin 2 due to genetic interventions are resistant to inflammation that would normally be induced by bacteria. Angiopoietin 1 has been shown to have anti inflammatory effects on isolated blood vessels in the laboratory.Previous work and our own preliminary data show that angiopoietin 2 levels are significantly higher in blood samples from patients with active vasculitis in comparison to control subjects. Furthermore we have novel data which shows that angiopoietin 2 affects a specific class of white cells involved in vascultis pathogenesis. Understanding the role of angiopoietins and targeting them will help alter the prognosis of the disease by causing less scarring of blood vessels and will hopefully lead to more targeted therapy which is much needed. Important questions we will address in this project include:- How do the blood vessels manipulate the inflammation in vasculitis by the production of angiopoietins?- How do angiopoietins impact on the kidney blood vessel cells themselves?- How are angiopoietins involved in recruitment of white blood cells crucial in vasculitis and how do they change the behaviour of the white blood cells?- How do angiopoietins affect the degree of inflammation in a rodent model of vasculitis?- What happens when we block the effect of angiopoietin 2 in a rodent model of vasculitis and may this be a useful treatment in patients ?