Targeting Syk-activated B cells in murine and human chronic graft-versus-host disease

Blood. 2015 Jun 25;125(26):4085-94. doi: 10.1182/blood-2014-08-595470. Epub 2015 Apr 7.

Abstract

Novel therapies for chronic graft-versus-host disease (cGVHD) are needed. Aberrant B-cell activation has been demonstrated in mice and humans with cGVHD. Having previously found that human cGVHD B cells are activated and primed for survival, we sought to further evaluate the role of the spleen tyrosine kinase (Syk) in cGVHD in multiple murine models and human peripheral blood cells. In a murine model of multiorgan system, nonsclerodermatous disease with bronchiolitis obliterans where cGVHD is dependent on antibody and germinal center (GC) B cells, we found that activation of Syk was necessary in donor B cells, but not T cells, for disease progression. Bone marrow-specific Syk deletion in vivo was effective in treating established cGVHD, as was a small-molecule inhibitor of Syk, fostamatinib, which normalized GC formation and decreased activated CD80/86(+) dendritic cells. In multiple distinct models of sclerodermatous cGVHD, clinical and pathological disease manifestations were not eliminated when mice were therapeutically treated with fostamatinib, though both clinical and immunologic effects could be observed in one of these scleroderma models. We further demonstrated that Syk inhibition was effective at inducing apoptosis of human cGVHD B cells. Together, these data demonstrate a therapeutic potential of targeting B-cell Syk signaling in cGVHD.

MeSH terms

  • Aminopyridines
  • Animals
  • B-Lymphocytes / enzymology*
  • B-Lymphocytes / immunology
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology
  • Female
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Graft vs Host Disease / enzymology*
  • Graft vs Host Disease / immunology
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Lymphocyte Activation / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Morpholines
  • Oxazines / pharmacology
  • Protein-Tyrosine Kinases / metabolism*
  • Pyridines / pharmacology
  • Pyrimidines
  • Syk Kinase

Substances

  • Aminopyridines
  • Enzyme Inhibitors
  • Intracellular Signaling Peptides and Proteins
  • Morpholines
  • Oxazines
  • Pyridines
  • Pyrimidines
  • Protein-Tyrosine Kinases
  • SYK protein, human
  • Syk Kinase
  • Syk protein, mouse
  • fostamatinib