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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Flynn, R; Allen, JL; Luznik, L; MacDonald, KP; Paz, K; Alexander, KA; Vulic, A; Du, J; Panoskaltsis-Mortari, A; Taylor, PA; Poe, JC; Serody, JS; Murphy, WJ; Hill, GR; Maillard, I; Koreth, J; Cutler, CS; Soiffer, RJ; Antin, JH; Ritz, J; Chao, NJ; Clynes, RA; Sarantopoulos, S; Blazar, BR

Published Date

  • June 25, 2015

Published In

Volume / Issue

  • 125 / 26

Start / End Page

  • 4085 - 4094

PubMed ID

  • 25852057

Pubmed Central ID

  • 25852057

Electronic International Standard Serial Number (EISSN)

  • 1528-0020

Digital Object Identifier (DOI)

  • 10.1182/blood-2014-08-595470

Language

  • eng

Conference Location

  • United States