Acute graft-versus-host disease (GvHD) limits the applicability of allogeneic 
hematopoietic cell transplantation for the treatment of leukemia. GvHD occurs as 
a consequence of multiple activating events in antigen-presenting cells (APCs) 
and T cells (Tcs). Spleen tyrosine kinase (Syk) is an intracellular non-receptor 
tyrosine kinase involved in multiple signaling events of immune cells. 
Therefore, we hypothesized that Syk may be a promising target to inhibit GvHD, 
which involves activation of different immune cell populations. In vivo 
expansion of luciferase(+) donor Tcs in mice developing GvHD was reduced by 
treatment with the Syk inhibitor Fostamatinib, which led to increased survival 
and reduced histologically confirmed GvHD severity. Importantly, in vivo and in 
vitro cytotoxicity against leukemia target cells and anti-murine cytomegalovirus 
immune responses were not impacted by Fostamatinib. In APCs Syk inhibition 
reduced the expression of costimulatory molecules and disrupted cytoskeletal 
organization with consecutive APC migratory defects in vitro and in vivo while 
phagocytic activity remained intact. On the basis of these immunomodulatory 
effects on different cell populations, we conclude that Syk targeting in 
alloantigen-activated Tcs and APCs with pharmacologic inhibitors, already 
applied successfully in anti-lymphoma therapy, has clinical potential to reduce 
GvHD, especially as anti-leukemia and anti-viral immunity were preserved.