title: Targeting Syk-activated B cells in murine and human chronic graft-versus-host disease.
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.
authors: Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN;
authors: Ryan
authors: R
authors: Flynn
authors: Division of Hematological Malignancies and Cellular Therapy, Department of Medicine, Duke Cancer Institute, Duke University, Durham, NC;
authors: Jessica L
authors: JL
authors: Allen
authors: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, Baltimore, MD;
authors: Leo
authors: L
authors: Luznik
authors: Department of Immunology, Queensland Institute of Medical Research, Brisbane, Australia;
authors: Kelli P
authors: KP
authors: MacDonald
authors: Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN;
authors: Katelyn
authors: K
authors: Paz
authors: Department of Immunology, Queensland Institute of Medical Research, Brisbane, Australia;
authors: Kylie A
authors: KA
authors: Alexander
authors: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, Baltimore, MD;
authors: Ante
authors: A
authors: Vulic
authors: Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN;
authors: Jing
authors: J
authors: Du
authors: Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN;
authors: Angela
authors: A
authors: Panoskaltsis-Mortari
authors: Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN;
authors: Patricia A
authors: PA
authors: Taylor
authors: Division of Hematological Malignancies and Cellular Therapy, Department of Medicine, Duke Cancer Institute, Duke University, Durham, NC;
authors: Jonathan C
authors: JC
authors: Poe
authors: Division of Hematology/Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC;
authors: Jonathan S
authors: JS
authors: Serody
authors: Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, CA;
authors: William J
authors: WJ
authors: Murphy
authors: Department of Immunology, Queensland Institute of Medical Research, Brisbane, Australia;
authors: Geoffrey R
authors: GR
authors: Hill
authors: Division of Hematology-Oncology, Department of Internal Medicine, Life Sciences Institute, University of Michigan, Ann Arbor, MI;
authors: Ivan
authors: I
authors: Maillard
authors: Dana Farber Cancer Institute, Boston, MA; and.
authors: John
authors: J
authors: Koreth
authors: Dana Farber Cancer Institute, Boston, MA; and.
authors: Corey S
authors: CS
authors: Cutler
authors: Dana Farber Cancer Institute, Boston, MA; and.
authors: Robert J
authors: RJ
authors: Soiffer
authors: Dana Farber Cancer Institute, Boston, MA; and.
authors: Joseph H
authors: JH
authors: Antin
authors: Dana Farber Cancer Institute, Boston, MA; and.
authors: Jerome
authors: J
authors: Ritz
authors: Division of Hematological Malignancies and Cellular Therapy, Department of Medicine, Duke Cancer Institute, Duke University, Durham, NC;
authors: Nelson J
authors: NJ
authors: Chao
authors: Columbia University Medical Center, Department of Medicine and Department of Microbiology, Columbia University, New York, NY.
authors: Raphael A
authors: RA
authors: Clynes
authors: Division of Hematological Malignancies and Cellular Therapy, Department of Medicine, Duke Cancer Institute, Duke University, Durham, NC;
authors: Stefanie
authors: S
authors: Sarantopoulos
authors: Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN;
authors: Bruce R
authors: BR
authors: Blazar
mesh_terms: D000631:Aminopyridines; D000818:Animals; D001402:B-Lymphocytes / Q000201:enzymology* / Q000276:immunology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006086:Graft vs Host Disease / Q000201:enzymology* / Q000276:immunology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines; D010078:Oxazines / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines; D000072377:Syk Kinase
chemical_list: D000631:Aminopyridines; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D009025:Morpholines; D010078:Oxazines; D011725:Pyridines; D011743:Pyrimidines; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; C523665:fostamatinib