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

Ryan Flynn, Jessica L Allen, Leo Luznik, Kelli P MacDonald, Katelyn Paz, Kylie A Alexander, Ante Vulic, Jing Du, Angela Panoskaltsis-Mortari, Patricia A Taylor, Jonathan C Poe, Jonathan S Serody, William J Murphy, Geoffrey R Hill, Ivan Maillard, John Koreth, Corey S Cutler, Robert J Soiffer, Joseph H Antin, Jerome Ritz, Nelson J Chao, Raphael A Clynes, Stefanie Sarantopoulos, Bruce R Blazar

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 multi-organ system, non-sclerodermatous 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. BM-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 immunological 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.