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Spleen tyrosine kinase inhibition is an effective treatment for established vasculitis in a pre-clinical model.
Kidney International ( IF 19.6 ) Pub Date : 2020-01-16 , DOI: 10.1016/j.kint.2019.12.014
Stephen P McAdoo 1 , Maria Prendecki 1 , Anisha Tanna 1 , Tejal Bhatt 1 , Gurjeet Bhangal 1 , John McDaid 1 , Esteban S Masuda 2 , H Terence Cook 1 , Frederick W K Tam 1 , Charles D Pusey 1
Affiliation  

The anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV) are a group of life-threatening multi-system diseases characterized by necrotising inflammation of small blood vessels and crescentic glomerulonephritis. ANCA are thought to play a direct pathogenic role. Previous studies have shown that spleen tyrosine kinase (SYK) is phosphorylated during ANCA-induced neutrophil activation in vitro. However, the role of SYK in vivo is unknown. Here, we studied its role in the pathogenesis of experimental autoimmune vasculitis, a pre-clinical model of myeloperoxidase-ANCA-induced pauci-immune systemic vasculitis in the Wistar Kyoto rat. Up-regulation of SYK expression in inflamed renal and pulmonary tissue during early autoimmune vasculitis was confirmed by immunohistochemical and transcript analysis. R406, the active metabolite of fostamatinib, a small molecule kinase inhibitor with high selectivity for SYK, inhibited ANCA-induced pro-inflammatory responses in rat leucocytes in vitro. In an in vivo study, treatment with fostamatinib for 14 days after disease onset resulted in rapid resolution of urinary abnormalities, significantly improved renal and pulmonary pathology, and preserved renal function. Short-term exposure to fostamatinib did not significantly affect circulating myeloperoxidase-ANCA levels, suggesting inhibition of ANCA-induced inflammatory mechanisms in vivo. Finally, SYK expression was demonstrated within inflammatory glomerular lesions in ANCA-associated glomerulonephritis in patients, particularly within CD68+ve monocytes/macrophages. Thus, our data indicate that SYK inhibition warrants clinical investigation in the treatment of AAV.

中文翻译:

在临床前模型中,脾酪氨酸激酶抑制是对已建立的血管炎的有效治疗方法。

抗中性粒细胞胞浆抗体(ANCA)相关的血管炎(AAV)是一组威胁生命的多系统疾病,其特征是坏死了小血管的炎症和新月型肾小球肾炎。ANCA被认为起直接的致病作用。先前的研究表明,脾脏酪氨酸激酶(SYK)在体外ANCA诱导的中性粒细胞活化过程中被磷酸化。然而,SYK在体内的作用尚不清楚。在这里,我们研究了它在实验性自身免疫性血管炎的发病机理中的作用,该疾病是由髓过氧化物酶-ANCA诱导的Wistar Kyoto大鼠骨髓过氧化性免疫系统性血管炎的临床前模型。通过免疫组织化学和转录本分析证实了在早期自身免疫性血管炎期间发炎的肾脏和肺组织中SYK表达的上调。R406,fostamatinib(一种对SYK具有高选择性的小分子激酶抑制剂)的活性代谢产物可在体外抑制ANCA诱导的大鼠白细胞促炎反应。在一项体内研究中,在疾病发作后用Fostamatinib治疗14天可快速解决尿液异常,显着改善肾脏和肺部病理,并保留肾脏功能。短期接触福司他替尼不会显着影响循环中的髓过氧化物酶-ANCA水平,这表明体内抑制了ANCA诱导的炎症机制。最后,在患者ANCA相关性肾小球肾炎的炎性肾小球病变中,特别是在CD68 + ve单核细胞/巨噬细胞中,证实了SYK表达。从而,
更新日期:2020-01-16
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