Spleen tyrosine kinase (Syk) is a potent target for GvHD prevention at different cellular levels.
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.
Department of Medicine, Division of Hematology and Oncology, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg, Germany.
F
F
Leonhardt
K
K
Zirlik
M
M
Buchner
G
G
Prinz
A-K
AK
Hechinger
U V
UV
Gerlach
P
P
Fisch
A
A
Schmitt-Gräff
W
W
Reichardt
R
R
Zeiser
D000631:Aminopyridines; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D015153:Blotting, Western; D016026:Bone Marrow Transplantation; D002465:Cell Movement; D049109:Cell Proliferation; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections / Q000276:immunology / Q000821:virology; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control*; D020544:Graft vs Leukemia Effect; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007938:Leukemia / Q000276:immunology / Q000628:therapy*; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009025:Morpholines; D010078:Oxazines / Q000627:therapeutic use*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000627:therapeutic use*; D011743:Pyrimidines; D013154:Spleen / Q000201:enzymology*; D000072377:Syk Kinase; D013601:T-Lymphocytes / Q000276:immunology; D014184:Transplantation, Homologous
D000631:Aminopyridines; D047908:Intracellular Signaling Peptides and Proteins; D009025:Morpholines; D010078:Oxazines; D011725:Pyridines; D011743:Pyrimidines; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse; C523665:fostamatinib