Investigating the role of the novel Th17 cells in the pathogenesis of ANCA associated vasculitis...

l-r Steve Madincea, VF Board member presents grarnt award to Dr. Alan Salama

Title: Investigating the role of the novel TH17 cells in the pathogenesis of the ANCA associated vasculitis and their potential for immunomodulation.

Investigator: Alan David Salama, M.D.

Location: Hammersmith Hospital, London, UK

Timeline: January - December, 2009

Abstract:  ANCA-associated vasculitides (AAV) are relapsing remitting diseases in which an autoimmune response to certain leukocyte proteins is generated. Despite current immunotherapeutic strategies disease relapses are common in up to 50% of patients. There is evidence that T cell immune responses to the autoantigens are critical to disease pathogenesis, with T cells being found in the biopsies of affected tissues, identified in peripheral blood and involved in both granuloma formation and class switching of ANCA-IgG. Recently a novel T cell phenotype has been described as being fundamental for autoimmune disease, in which cells are characterized by the production of Interleukin-17(IL-17). We hypothesize that an auto-reactive antigen-specific Th17 cell population is present in AAV, impairs the generation of regulatory T cells, promotes tissue damage and underlies disease relapses. Moreover, these may be relatively resistant to conventional treatment and may be best targeted using more appropriate biological (anti-cytokine) agents which are currently being trialed in other autoimmune disease settings. This hypothesis will be tested by studying Th17 cells in human disease and in a recently described experimental model of ANCA associated glomerulonephritis, in which tolerance is broken to the autoantigen and disease localized to the kidney following neutrophil recruitment.

IL-17 levels in patient samples will be compared to that in controls and correlated to disease severity. The cytokine responses of PBMC to antigen stimulation will be characterized and renal biopsies examined for Th17 cells. Using an experimental model of ANCA-induced glomerulonephritis, the role of IL-17 and gamma-interferon in disease will be compared. We will investigate whether certain clinical strategies could be applied to treat disease, based on preventing the generation/expansion of Th17 cells by blockade of IL-6, IL-23 or IL-1. Using this more targeted approach, to prevent Th17 cell generation, relapse of disease might be prevented.

Lay Person Summary:  Auto-immune diseases are those caused by the body’s own immune system. A group of these are characterized by an antibody called anti-neutrophil cytoplasmic antibody (ANCA). They cause inflammation of blood vessels (vasculitis) which result in significant health problems such as kidney failure and lung disease. Like other autoimmune diseases, they often relapse, requiring repeated treatment with drugs that suppress the immune system but have serious side-effects. In patients with frequent relapses this treatment may be required for life, while even in patients who initially respond to therapy, one in five patients with kidney involvement will go on and develop end stage kidney disease, and ultimately up to half the patients will undergo some form of disease relapse. These relapses represent a significant challenge to treatment regimens, especially for patients with Wegener’s granulomatosis or those with Proteinase 3(PR3)-ANCA in whom relapse is more common.

Although we understand some of the events which perpetuate inflammation in the kidneys and lungs of

patients who have disease, little is known about what initially causes it and why it relapses. Based on published evidence, it is suggested that a newly recognized, but little understood immune pathway, involving specialist white blood cells releasing a chemical called interleukin-17, might underlie both the trigger for disease initiation and relapse. In this project, we will study the role of this pathway in ANCA-related kidney disease using patients and newly established experimental model systems. As we understand more about this pathway it should be possible to specifically target these cells, treat the disease more effectively and potentially prevent the development of disease relapse.