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

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    Authors
    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.
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    Issue Date
    2014-10-31
    Subjects
    spleen tyrosine kinase
    
    Metadata
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    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.
    Citation
    McAdoo SP, Reynolds J, Bhangal G, Smith J, McDaid JP, Tanna A, Jackson WD, Masuda ES, Cook HT, Pusey CD, Tam FWK (2014) 'Spleen tyrosine kinase inhibition attenuates autoantibody production and reverses experimental autoimmune GN', Journal of the American Society of Nephrology : JASN, 25 (10), pp.2291-302.
    Publisher
    American Society of Nephrology
    Journal
    Journal of the American Society of Nephrology : JASN
    URI
    http://hdl.handle.net/10547/623116
    DOI
    10.1681/ASN.2013090978
    PubMed ID
    24700868
    PubMed Central ID
    PMC4178438
    Additional Links
    https://jasn.asnjournals.org/content/25/10/2291
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4178438/
    Type
    Article
    Language
    en
    ISSN
    1533-3450
    ae974a485f413a2113503eed53cd6c53
    10.1681/ASN.2013090978
    Scopus Count
    Collections
    Biomedical and biological science

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