Imperial College London
Alternate

PROFESSOR H. TERENCE COOK

Faculty of Medicine, Department of Immunology and Inflammation

Emeritus Professor
 
 
 
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Contact

 

+44 (0)20 3313 2009t.h.cook

 
 
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Assistant

 

Miss Claudia Rocchi +44 (0)20 3313 2315

 
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Location

 

9N9Commonwealth BuildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{McAdoo:2014:10.1681/ASN.2013090978,
author = {McAdoo, SP and Reynolds, J and Bhangal, G and Smith, J and McDaid, JP and Tanna, A and Jackson, WD and Masuda, ES and Cook, HT and Pusey, CD and Tam, FWK},
doi = {10.1681/ASN.2013090978},
journal = {Journal of the American Society of Nephrology},
pages = {2291--2302},
title = {Spleen tyrosine kinase inhibition attenuates autoantibody production and reverses experimental autoimmune GN},
url = {http://dx.doi.org/10.1681/ASN.2013090978},
volume = {25},
year = {2014}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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.
AU  - McAdoo,SP
AU  - Reynolds,J
AU  - Bhangal,G
AU  - Smith,J
AU  - McDaid,JP
AU  - Tanna,A
AU  - Jackson,WD
AU  - Masuda,ES
AU  - Cook,HT
AU  - Pusey,CD
AU  - Tam,FWK
DO  - 10.1681/ASN.2013090978
EP  - 2302
PY  - 2014///
SN  - 1046-6673
SP  - 2291
TI  - Spleen tyrosine kinase inhibition attenuates autoantibody production and reverses experimental autoimmune GN
T2  - Journal of the American Society of Nephrology
UR  - http://dx.doi.org/10.1681/ASN.2013090978
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000342403800018&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - http://hdl.handle.net/10044/1/19627
VL  - 25
ER  -
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