MICA: Myeloperoxidase inhibition as a potential therapy in anti-neutrophil cytoplasmic antibody vasculitis

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Antibodies are circulating proteins in the immune system that normally fight infection. The immune system can malfunction and in some patients antibodies stick to white blood cells and cause a form of vasculitis or blood vessel inflammation. This can affect joints, lungs, kidneys, skin and other tissues and occurs most often in older adults. The antibodies bind in particular to the proteins myeloperoxidase (MPO) proteinase 3 which are found in certain white blood cells. The antibodies are thought to play a key role in causing disease. MPO is a protein in white blood cells that normally fights infection and can also cause tissue inflammation in certain diseases. Thus blocking MPO may be beneficial in inflammatory disease such as vasculitis. The proposed study will define whether the MPO inhibitor AZD5904 is effective in reducing disease onset and/or development, and elucidate potential mechanisms. Our hypothesis is that inhibition of MPO enyzme activity will be an effective therapy for vasculitis. Using the MPO inhibitor AZD5904, we plan to test this through a combination of experiments using human and murine white blood cells in vitro and murine in vivo models. In the first part of the research, we will use an in vivo model of anti-MPO vasculitis in mice. In addition to examining the therapeutic efficacy of AZD5904 we will explore the mechanisms of this effect with particular reference to the same type of white blood cell that will be studied in the in vitro work with patient samples. We will also aim to understand the effect of anti-MPO antibody, purified from the blood of patients with vasculitis, on human white blood cells. Our preliminary data suggest important effects on the responses of a particular type of white blood cell that are relevant to disease. We aim to understand the mechanism by which these effects depend on MPO enzyme, and to link this to potential consequences for disease expression in the murine model. This will place us in an ideal position to proceed to clinical trials and this would naturally follow from the plan of work contained in the current application.