Spleen tyrosine kinase inhibition attenuates autoantibody production and reverses experimental autoimmune GN.
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.
Renal and Vascular Inflammation Section, and.
Stephen P
SP
McAdoo
Department of Biomedical/Forensic Science, University of Bedfordshire, Befordshire, United Kingdom; and.
John
J
Reynolds
Renal and Vascular Inflammation Section, and.
Gurjeet
G
Bhangal
Renal and Vascular Inflammation Section, and.
Jennifer
J
Smith
Renal and Vascular Inflammation Section, and.
John P
JP
McDaid
Renal and Vascular Inflammation Section, and.
Anisha
A
Tanna
Renal and Vascular Inflammation Section, and.
William D
WD
Jackson
Department of Immunology, Rigel Pharmaceuticals, South San Francisco, California.
Esteban S
ES
Masuda
Centre for Complement and Inflammation Research, Department of Medicine, Imperial College London, London, United Kingdom;
H Terence
HT
Cook
Renal and Vascular Inflammation Section, and.
Charles D
CD
Pusey
Renal and Vascular Inflammation Section, and f.tam@imperial.ac.uk.
Frederick W K
FW
Tam
D000631:Aminopyridines; D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000276:immunology* / Q000517:prevention & control*; D000917:Antibody Formation / Q000187:drug effects*; D001323:Autoantibodies / Q000097:blood; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009025:Morpholines; D010078:Oxazines / Q000494:pharmacology / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines; D011921:Rats, Inbred WKY; D013154:Spleen / Q000187:drug effects; D000072377:Syk Kinase
D000631:Aminopyridines; D001323:Autoantibodies; D047908:Intracellular Signaling Peptides and Proteins; D009025:Morpholines; D010078:Oxazines; D011725:Pyridines; D011743:Pyrimidines; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606898:Syk protein, rat; C523665:fostamatinib