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

Flynn, Ryan, Allen, Jessica L., Luznik, Leo, MacDonald, Kelli P., Paz, Katelyn, Alexander, Kylie A., Vulic, Ante, Du, Jing, Panoskaltsis-Mortari, Angela, Taylor, Patricia A., Poe, Jonathan C., Serody, Jonathan S., Murphy, William J., Hill, Geoffrey R., Maillard, Ivan, Koreth, John, Cutler, Corey S., Soiffer, Robert J., Antin, Joseph H., Ritz, Jerome, Chao, Nelson J., Clynes, Raphael A., Sarantopoulos, Stefanie and Blazar, Bruce R. (2015) Targeting Syk-activated B cells in murine and human chronic graft-versus-host disease. Blood, 125 26: 4085-4094. doi:10.1182/blood-2014-08-595470


Author Flynn, Ryan
Allen, Jessica L.
Luznik, Leo
MacDonald, Kelli P.
Paz, Katelyn
Alexander, Kylie A.
Vulic, Ante
Du, Jing
Panoskaltsis-Mortari, Angela
Taylor, Patricia A.
Poe, Jonathan C.
Serody, Jonathan S.
Murphy, William J.
Hill, Geoffrey R.
Maillard, Ivan
Koreth, John
Cutler, Corey S.
Soiffer, Robert J.
Antin, Joseph H.
Ritz, Jerome
Chao, Nelson J.
Clynes, Raphael A.
Sarantopoulos, Stefanie
Blazar, Bruce R.
Title Targeting Syk-activated B cells in murine and human chronic graft-versus-host disease
Journal name Blood   Check publisher's open access policy
ISSN 1528-0020
0006-4971
Publication date 2015-06-25
Year available 2015
Sub-type Article (original research)
DOI 10.1182/blood-2014-08-595470
Open Access Status Not yet assessed
Volume 125
Issue 26
Start page 4085
End page 4094
Total pages 10
Place of publication Washington, DC, United States
Publisher American Society of Hematology
Language eng
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, 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. 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.
Formatted 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.
Keyword Hematology
Hematology
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID P01 CA142106-06A1
R01 HL126530
P01 AI 056299
6458-15
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
 
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