Spleen tyrosine kinase inhibition attenuates autoantibody production and reverses experimental autoimmune GN
File(s)
Supporting information
Accepted version
Author(s)
Type
Journal Article
Abstract
Spleen tyrosine kinase (SYK) has an important role in immunoreceptor signaling, and SYK inhibition has accordingly attenuated immune-mediated injury in several in vivo models. However, the effect of SYK inhibition on autoantibody production remains unclear, and SYK inhibition has not been studied in an autoimmune model of renal disease. We, therefore, studied the effect of SYK inhibition in experimental autoimmune GN, a rodent model of antiglomerular basement membrane disease. We show glomerular SYK expression and activation by immunohistochemistry in both experimental and clinical disease, and we show that treatment with fostamatinib, a small molecule kinase inhibitor selective for SYK, completely prevents the induction of experimental autoimmune GN. In established experimental disease, introduction of fostamatinib treatment led to cessation of autoantibody production, reversal of renal injury, preservation of biochemical renal function, and complete protection from lung hemorrhage. B cell ELISpot and flow cytometric analysis suggest that short-term fostamatinib treatment inhibits the generation and activity of antigen-specific B cells without affecting overall B-cell survival. Additionally, fostamatinib inhibited proinflammatory cytokine production by nephritic glomeruli ex vivo and cultured bone marrow-derived macrophages in vitro, suggesting additional therapeutic effects independent of effects on autoantibody production that are likely related to inhibited Fc receptor signaling within macrophages in diseased glomeruli. Given these encouraging results in an in vivo model that is highly applicable to human disease, we believe clinical studies targeting SYK in GN are now warranted.
Date Issued
2014-10-01
Date Acceptance
2014-01-31
Citation
Journal of the American Society of Nephrology, 2014, 25 (10), pp.2291-2302
ISSN
1046-6673
Publisher
American Society of Nephrology
Start Page
2291
End Page
2302
Journal / Book Title
Journal of the American Society of Nephrology
Volume
25
Issue
10
Copyright Statement
© 2014 by the American Society of Nephrology
Sponsor
Medical Research Council (MRC)
Medical Research Council (MRC)
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000342403800018&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Grant Number
G0901997
G0400443
Subjects
Science & Technology
Life Sciences & Biomedicine
Urology & Nephrology
EXPERIMENTAL CRESCENTIC GLOMERULONEPHRITIS
B-CELL DEVELOPMENT
RHEUMATOID-ARTHRITIS
RAT ALPHA-3(IV)NC1
BASEMENT-MEMBRANE
MESANGIAL CELLS
SYK INHIBITOR
RENAL INJURY
INFLAMMATION
MACROPHAGES
Publication Status
Published
Date Publish Online
2014-09-30