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Spleen tyrosine kinase inhibition in the treatment of autoimmune, allergic and autoinflammatory diseases

By Omer N Pamuk and George C Tsokos


Spleen tyrosine kinase (Syk) is involved in the development of the adaptive immune system and has been recognized as being important in the function of additional cell types, including platelets, phagocytes, fibroblasts, and osteoclasts, and in the generation of the inflammasome. Preclinical studies presented compelling evidence that Syk inhibition may have therapeutic value in the treatment of rheumatoid arthritis and other forms of arthritis, systemic lupus erythematosus, autoimmune cytopenias, and allergic and autoinflammatory diseases. In addition, Syk inhibition may have a place in limiting tissue injury associated with organ transplant and revascularization procedures. Clinical trials have documented exciting success in the treatment of patients with rheumatoid arthritis, autoimmune cytopenias, and allergic rhinitis. While the extent and severity of side effects appear to be limited so far, larger studies will unravel the risk involved with the clinical benefit

Topics: Review
Publisher: BioMed Central
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Provided by: PubMed Central

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  1. (2002). A Syk-selective tyrosine kinase inhibitor, attenuated antigen challenge of guinea pig airways in vitro.
  2. (2005). A: Src and Syk kinases: key regulators of phagocytic cell activation. Trends Immunol
  3. (1997). AL: A critical role for Syk in signal transduction and phagocytosis mediated by Fcgamma receptors on macrophages. J Med
  4. (2009). An oral Syk kinase inhibitor in the treatment of rheumatoid arthritis (RA): a 3 month randomized placebo controlled phase 2 study in patients with active RA who had failed biologic agents (abstract). Arthritis Rheum
  5. (2008). An orally bioavailable spleen tyrosine kinase inhibitor delays disease progression and prolongs survival in murine lupus. Arthritis Rheum
  6. (2002). Blanchette VS: Immune thrombocytopeic purpura.
  7. (2007). Brahn E: Infl ammation and bone erosion are suppressed in models of rheumatoid arthritis following treatment with a novel Syk inhibitor. Clin Immunol
  8. (2009). Bussel JB: Of mice and men: an open –label pilot study for treatment of immune thrombocytopenic purpura by an inhibitor of Syk. Blood
  9. (2008). CARD9 signaling in the innate immune response.
  10. (2004). E: Targeting Syk as a treatment for allergic and autoimmune diseases. Expert Opin Investig Drugs
  11. (2005). EB: An intranasal Syk-kinase inhibitor (R112) improves the symptoms of seasonal allergic rhinitis in a park environment. J Allergy Clin Immunol
  12. (2006). ES: R406, an orally available spleen tyrosine kinase inhibitor blocks Fc receptor signaling and reduces immune complex-mediated infl ammation. J Pharmacol Exp Ther
  13. (2006). EW: Inhibition of spleen tyrosine kinase prevents mast cell activation and airway hyperresponsiveness.
  14. (2006). EW: Syk activation in dendritic cells is essential for airway hyperresponsiveness and infl ammation.
  15. (2002). Geahlen RL: Regulation of signaling in B through the phosphorylation of Syk on linker region tyrosines. A for negative signaling by the Lyn tyrosine kinase.
  16. (2006). Gout-associated uricacid crystals activate the NALP3 infl ammasome. Nature
  17. (2007). GR: Immunotoxicity assessment for the novel Spleen tyrosine kinase inhibitor R406. Toxicol Appl Pharmacol
  18. (2008). Grossbard E: Treatment of rheumatoid arthritis with a Syk kinase inhibitor: a twelve-week, randomized, placebo-controlled trial. Arthritis Rheum
  19. (2006). HS: Mast cell inhibitor R112 is well tolerated and aff ects prostaglandin D2 but not other mediators, symptoms, or nasal volumes in a nasal challenge model of allergic rhinitis. Allergy Asthma Proc
  20. (2001). IgG Fc receptors. Annu Rev Immunol
  21. (2009). Inoue O: Novel interactions in platelet biology: CLEC2/podoplanin and laminin/GPVI.
  22. (2003). KB: The orally available spleen tyrosine kinase inhibitor 2-[7-(3,4-Dimethhoxyphenyl)–imidazo [1,2-c]pyrimidin-5-ylamino] nicotinamide Dihydrochloride (BAY 61-3606) blocks antigeninduced airway infl ammation in rodents.
  23. (2006). Kivitz AJ: A phase I randomized, double-blind, placebo-controlled, pharmacokinetic study of R788/406 and methotrexate in sixteen patients with rheumatoid arthritis. Arthritis Rheum
  24. (2010). MA: Inhibition of Syk with fostamatinib disodium has signifi cant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood
  25. (2010). Magilavy D: Treatment of rheumatoid arthritis (RA) with an oral Syk kinase inhibitor: a month randomized placebo controlled phase 2b study in patients with active RA on chronic methotrexate (abstract).
  26. (2003). ML: Regulation of blood and lymphatic vascular separation by signaling proteins SLP-76 and Syk. Science
  27. (2004). Modulation of the Fcepsilon receptor I signaling by tyrosine kinase inhibitors: search for therapeutic targets of infl ammatory and allergy diseases. Curr Pharm Des
  28. (2010). Monosodium urate crystals in infl ammation and immunity. Immunol Rev
  29. (2001). Naccache PH: Crystalinduced neutrophil activation. VII. Involvement of Syk in the responses to monosodium urate crystals.
  30. (1994). Parslow TG: Human severe combined immunodefi ciency due to a defect in ZAP-70, a T cell tyrosine kinase. Science
  31. (1998). Pawson T: The Syk protein kynase is essential for cgamma receptor signaling in macrophages and neutrophils. Mol Cell Biol
  32. (2008). PJ: Identifi cation of FcγRIIa as the ITAM-bearing receptor mediating αIIbβ3 outside-in integrin signaling in human platelets. Blood
  33. (2006). PP: A novel spleen tyrosine kinase inhibitor blocks c-Jun N-terminal kinase-mediated gene expression in synoviocytes. J Pharmacol Exp Ther
  34. (2005). Role of ITAM-containing adapter proteins and their receptors in the immune system and bone. Immunol Rev
  35. (2006). Scharff etter-Kochanek K, Walzog B: The Vav binding site of the non-receptor tyrosine kinase Syk at Tyr 348 is critical for β2 integrin (CD11/CD18)-mediated neutrophil migration. Blood
  36. (2006). SP: A novel syk-dependent mechanism of platelet activation by the C-type lectin receptor CLEC-2. Blood
  37. (1997). SP: The Fc receptor γ-chain and the tyrosine kinase Syk are essential for activation of mouse platelets by collagen.
  38. (2001). Structure and function of Syk protein-tyrosine kinase.
  39. (2008). Syk inhibitors as treatment for allergic diseases. Pulmon Pharmacol Ther
  40. (2010). Syk kinase signaling and the Nlpr3 infl ammasome in antifungal immunity.
  41. (2009). Syk kinase signaling couples to the Nlpr3 infl ammasome for anti-fungal host defence. Nature
  42. (2004). T: Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homestasis. Nature
  43. (2010). Tam FWK: A spleen tyrosine kinase inhibitor reduces the severity of established glomerulonephritis.
  44. (2007). Teitelbaum SL: Syk, c-Src, the αIIbβ3 outside-in integrin signaling in human platelets.
  45. (2004). The immunomodulatory adapter proteins DAP12 and Fc receptor gamma chain (FcRgamma) regulate development of functional osteoclasts through the Syk tyrosine kinase.
  46. (2001). Tsokos GC: Fc epsilon receptor type I gamma chain replaces the defi cient T cell receptor zeta chain in T cells of patients with systemic lupus erythematosus. Arthritis Rheum
  47. (2010). Tsokos GC: Spleen tyrosine kinase inhibition prevents tissue damage after ischemiareperfusion.
  48. (2010). Tsokos GC: Spleen tyrosine kinase: an Src family of non-receptor kinase has multiple functions and represents a valuable therapeutic target in the treatment of autoimmune and infl ammatory diseases. Autoimmunity
  49. (2010). Tsokos GC: Suppression of skin and kidney disease by inhibition of spleen tyrosine kinase in lupus-prone mice. Arthritis Rheum
  50. (2007). Tsokos GC: Syk kinase as a treatment target for therapy in autoimmune diseases. Clin Immunol
  51. (2010). Tybulewicz LJ: The Syk tyrosine kinase: a crucial player in diverse biological functions. Nat Rev
  52. (1996). Tybulewicz VL: Critical role for the tyrosine kinase Syk in signaling through the high affi nity IgE receptor of mast cells. Oncogene
  53. (1995). Tybulewicz VL: Perinatal lethality and blocked B-cell development in mice lacking the tyrosine kinase Syk. Nature
  54. (2000). Tybulewicz VL: Tyrosine kinase Syk: essential functions for immunoreceptor signalling. Immunol Today
  55. (2003). Tybulewicz VL: Unexpected requirement for ZAP-70 in pre-B cell development and allelic exclusion. Immunity
  56. (2009). Tyrosine kinases and their substrates in B lymphocytes. Immunol Rev
  57. (2005). Valentine MD: Clinical practice. Allergic rhinitis.
  58. (2007). Weiss A: Distinct roles for Syk and ZAP-70 during early thymocyte development.
  59. (2009). WS: Tumor necrosis factor alpha-induced interleukin-32 is positively regulated via the Syk/ protein kinase Cdelta/JNK pathway in rheumatoid synovial fi broblasts. Arthritis Rheum
  60. (2006). Yamamura H: Complement-mediated phagocytosis - The role of Syk.
  61. (2009). Yamamura H: Protein tyrosine kinase, Syk: a key player in phagocytic cells.
  62. (2006). Yamamura H: Protein-tyrosine kinase, Syk is required for pathogen engulfment in complement-mediated phagocytosis. Blood