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Spleen tyrosine kinase inhibition attenuates autoantibody production and reverses experimental autoimmune GN

  • Stephen P. McAdoo
    ,
  • John Reynolds
    ,
  • Gurjeet Bhangal
    ,
  • Jennifer Smith
    ,
  • John P. McDaid
    ,
  • Anisha Tanna
  • Imperial College Healthcare NHS Trust
    ,
  • Rigel Pharmaceuticals Inc.
    ,
  • Imperial College London
Research Output: Contribution to journal Article Peer-review

Sustainable Development Goals

  • SDG 3 - Good Health and Well-being
    SDG 3 Good Health and Well

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.

Publication Information

Output type

Research Output: Contribution to journal Article Peer-review

Original language

English

Pages from-to (Number of pages)

Pages 2291-302

Journal (Volume, Issue Number)

Journal of the American Society of Nephrology (Volume 25, Issue 10)

Publication milestones

  • Accepted/In press - 31/01/2014
  • Published - 31/10/2014

Publication status

Published - 31/10/2014

ISSN

1046-6673

External Publication IDs

  • handle.net: 10547/623116
  • Scopus: 84921811878

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