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

抗体是免疫系统中的循环蛋白质，通常用于对抗感染。免疫系统可能会出现故障，在某些患者中，抗体会附着在白细胞上，导致某种形式的脉管炎或血管炎症。这会影响关节、肺、肾、皮肤和其他组织，最常发生在老年人身上。抗体特别与髓过氧化物酶(MPO)蛋白结合，这种蛋白存在于某些白血球中。这些抗体被认为在致病过程中起着关键作用。MPO是白细胞中的一种蛋白质，通常可以对抗感染，也可以在某些疾病中引起组织炎症。因此，阻断MPO可能对血管炎等炎症性疾病有益。这项拟议的研究将确定MPO抑制剂AZD5904在减少疾病发生和/或发展方面是否有效，并阐明潜在的机制。我们的假设是，抑制MPO Enyzme活性将是治疗血管炎的有效方法。使用MPO抑制剂AZD5904，我们计划通过使用人和小鼠白细胞体外和小鼠体内模型的组合实验来测试这一点。在研究的第一部分，我们将使用小鼠体内抗MPO血管炎的模型。除了检查AZD5904的治疗效果外，我们还将特别参考将在患者样本体外工作中研究的相同类型的白细胞，来探索这种效果的机制。我们还将致力于了解从血管炎患者的血液中提纯的抗MPO抗体对人类白细胞的影响。我们的初步数据表明，与疾病相关的一种特定类型的白细胞对反应有重要影响。我们的目标是了解这些效应依赖于MPO酶的机制，并将其与小鼠模型中疾病表达的潜在后果联系起来。这将使我们处于进行临床试验的理想位置，这自然会遵循当前申请中包含的工作计划。

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.