Spleen tyrosine kinase inhibition is an effective treatment for established vasculitis in a pre-clinical model
| Autor: | Charles D. Pusey, John P. McDaid, Anisha Tanna, Frederick W.K. Tam, Stephen P. McAdoo, H. Terence Cook, Esteban Masuda, Maria Prendecki, Tejal Bhatt, Gurjeet Bhangal |
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| Přispěvatelé: | Vasculitis UK, The Academy of Medical Sciences, Medical Research Council (MRC), Wellcome Trust, Imperial College Healthcare NHS Trust |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
030232 urology & nephrology Syk experimental models Inflammation Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis Fostamatinib urologic and male genital diseases Article vasculitis Antibodies Antineutrophil Cytoplasmic Pathogenesis 03 medical and health sciences 0302 clinical medicine medicine Animals Humans Syk Kinase SYK kinase inhibitors cardiovascular diseases Peroxidase business.industry CD68 ANCA Glomerulonephritis 1103 Clinical Sciences Urology & Nephrology medicine.disease Rats 030104 developmental biology Nephrology Cancer research medicine.symptom business Vasculitis glomerulonephritis medicine.drug Systemic vasculitis |
| Zdroj: | Kidney International |
| Popis: | 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. Graphical abstract |
| Databáze: | OpenAIRE |
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