Abstract
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.
Highlights
The anti-neutrophil cytoplasm antibody (ANCA)–associated vasculitides are a group of rare diseases characterized by the inflammation of blood vessels, crescentic glomerulonephritis, and lung hemorrhage
We have investigated the effect of spleen tyrosine kinase (SYK) inhibition in an experimental model of myeloperoxidase (MPO)-ANCA– induced systemic vasculitis that was developed in our laboratory.[9,10]
The findings reported here are consistent with our previous work showing that SYK inhibition with fostamatinib is effective in both preventing and treating established crescentic glomerulonephritis in anti–glomerular basement membrane disease models.[4,5]
Summary
The anti-neutrophil cytoplasm antibody (ANCA)–associated vasculitides are a group of rare diseases characterized by the inflammation of blood vessels, crescentic glomerulonephritis, and lung hemorrhage. Spleen tyrosine kinase (SYK) is a cytosolic protein tyrosine kinase that is expressed in most leucocyte populations, where it has diverse immune functions It has a well characterized role in mediating signaling from classical immunoreceptors such as the B-cell receptor and the Fc receptor, and from some integrins and C-type lectins.[1] Targeting SYK has emerged as a potential treatment approach for a variety of immune and inflammatory diseases,[2] and a number of specific SYK inhibitors are in development.[3] We have previously shown that fostamatinib, a small molecule kinase inhibitor with selectivity for SYK, is an effective treatment in experimental models of immunecomplex glomerulonephritis.[4,5] SYK mediates proinflammatory responses induced by IgA1 derived from patients with IgA nephropathy,[6] and full results from a Phase II clinical study assessing SYK inhibition with fostamatinib in proliferative IgA nephropathy are awaited (NCT02112838). In contrast to our previous studies in immune-complex glomerulonephritis, this model has a distinct pauci-immune mechanism of tissue injury, similar to that in AAV
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