Spleen Tyrosine Kinase Inhibition Attenuates Autoantibody... : Journal of the American Society of Nephrology (original) (raw)

Basic Research

Spleen Tyrosine Kinase Inhibition Attenuates Autoantibody Production and Reverses Experimental Autoimmune GN

McAdoo, Stephen P.*; Reynolds, John†; Bhangal, Gurjeet*; Smith, Jennifer*; McDaid, John P.*; Tanna, Anisha*; Jackson, William D.*; Masuda, Esteban S.‡; Cook, H. Terence§; Pusey, Charles D.*; Tam, Frederick W.K.*

*Renal and Vascular Inflammation Section, and

§Centre for Complement and Inflammation Research, Department of Medicine, Imperial College London, London, United Kingdom;

†Department of Biomedical/Forensic Science, University of Bedfordshire, Befordshire, United Kingdom; and

‡Department of Immunology, Rigel Pharmaceuticals, South San Francisco, California

C.D.P. and F.W.K.T. contributed equally to this work.

Correspondence: Dr. Frederick W.K. Tam, Renal and Vascular Inflammation Section, Department of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK. Email: [email protected]

Received September 16, 2013

Accepted January 31, 2014

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.