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 RitzNelson J. Chao, Raphael A. Clynes, Stefanie Sarantopoulos, Bruce R. Blazar

Research output: Contribution to journalArticle

46 Citations (Scopus)

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 humancGVHDBcells 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. Bonemarrow-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 CD80/861 dendritic cells. Inmultiple distinctmodels of sclerodermatouscGVHD, clinical and pathological diseasemanifestationswere not eliminated when mice were therapeutically treated with fostamatinib, though both clinical and immunologic effects could be observed in one of these sclerodermamodels. We furtherdemonstratedthatSykinhibitionwaseffectiveat inducingapoptosisofhumancGVHDBcells.Together, these data demonstrate a therapeutic potential of targeting B-cell Syk signaling in cGVHD.

Original languageEnglish (US)
Pages (from-to)4085-4094
Number of pages10
JournalBlood
Volume125
Issue number26
DOIs
StatePublished - Jun 25 2015

Fingerprint

Graft vs Host Disease
Grafts
Protein-Tyrosine Kinases
B-Lymphocytes
Cells
Germinal Center
Bronchiolitis Obliterans
Chemical activation
Dendritic Cells
T-cells
Disease Progression
Syk Kinase
Blood Cells
T-Lymphocytes
Blood
Survival
Antibodies
Therapeutics
Molecules

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Flynn, R., Allen, J. L., Luznik, L., MacDonald, K. P., Paz, K., Alexander, K. A., ... Blazar, B. R. (2015). Targeting Syk-activated B cells in murine and human chronic graft-versus-host disease. Blood, 125(26), 4085-4094. https://doi.org/10.1182/blood-2014-08-595470

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; Blazar, Bruce R.

In: Blood, Vol. 125, No. 26, 25.06.2015, p. 4085-4094.

Research output: Contribution to journalArticle

Flynn, R, Allen, JL, Luznik, L, MacDonald, KP, Paz, K, Alexander, KA, Vulic, A, Du, J, Panoskaltsis-Mortari, A, Taylor, PA, Poe, JC, Serody, JS, Murphy, WJ, Hill, GR, Maillard, I, Koreth, J, Cutler, CS, Soiffer, RJ, Antin, JH, Ritz, J, Chao, NJ, Clynes, RA, Sarantopoulos, S & Blazar, BR 2015, 'Targeting Syk-activated B cells in murine and human chronic graft-versus-host disease', Blood, vol. 125, no. 26, pp. 4085-4094. https://doi.org/10.1182/blood-2014-08-595470
Flynn R, Allen JL, Luznik L, MacDonald KP, Paz K, Alexander KA et al. Targeting Syk-activated B cells in murine and human chronic graft-versus-host disease. Blood. 2015 Jun 25;125(26):4085-4094. https://doi.org/10.1182/blood-2014-08-595470
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. / Targeting Syk-activated B cells in murine and human chronic graft-versus-host disease. In: Blood. 2015 ; Vol. 125, No. 26. pp. 4085-4094.
@article{7e9a899f03344418a1cf46e87c9448ff,
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 humancGVHDBcells 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. Bonemarrow-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 CD80/861 dendritic cells. Inmultiple distinctmodels of sclerodermatouscGVHD, clinical and pathological diseasemanifestationswere not eliminated when mice were therapeutically treated with fostamatinib, though both clinical and immunologic effects could be observed in one of these sclerodermamodels. We furtherdemonstratedthatSykinhibitionwaseffectiveat inducingapoptosisofhumancGVHDBcells.Together, these data demonstrate a therapeutic potential of targeting B-cell Syk signaling in cGVHD.",
author = "Ryan Flynn and Allen, {Jessica L.} and Leo Luznik and MacDonald, {Kelli P.} and Katelyn Paz and Alexander, {Kylie A.} and Ante Vulic and Jing Du and Angela Panoskaltsis-Mortari and Taylor, {Patricia A.} and Poe, {Jonathan C.} and Serody, {Jonathan S.} and Murphy, {William J} and Hill, {Geoffrey R.} and Ivan Maillard and John Koreth and Cutler, {Corey S.} and Soiffer, {Robert J.} and Antin, {Joseph H.} and Jerome Ritz and Chao, {Nelson J.} and Clynes, {Raphael A.} and Stefanie Sarantopoulos and Blazar, {Bruce R.}",
year = "2015",
month = "6",
day = "25",
doi = "10.1182/blood-2014-08-595470",
language = "English (US)",
volume = "125",
pages = "4085--4094",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "26",

}

TY - JOUR

T1 - Targeting Syk-activated B cells in murine and human chronic graft-versus-host disease

AU - Flynn, Ryan

AU - Allen, Jessica L.

AU - Luznik, Leo

AU - MacDonald, Kelli P.

AU - Paz, Katelyn

AU - Alexander, Kylie A.

AU - Vulic, Ante

AU - Du, Jing

AU - Panoskaltsis-Mortari, Angela

AU - Taylor, Patricia A.

AU - Poe, Jonathan C.

AU - Serody, Jonathan S.

AU - Murphy, William J

AU - Hill, Geoffrey R.

AU - Maillard, Ivan

AU - Koreth, John

AU - Cutler, Corey S.

AU - Soiffer, Robert J.

AU - Antin, Joseph H.

AU - Ritz, Jerome

AU - Chao, Nelson J.

AU - Clynes, Raphael A.

AU - Sarantopoulos, Stefanie

AU - Blazar, Bruce R.

PY - 2015/6/25

Y1 - 2015/6/25

N2 - 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 humancGVHDBcells 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. Bonemarrow-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 CD80/861 dendritic cells. Inmultiple distinctmodels of sclerodermatouscGVHD, clinical and pathological diseasemanifestationswere not eliminated when mice were therapeutically treated with fostamatinib, though both clinical and immunologic effects could be observed in one of these sclerodermamodels. We furtherdemonstratedthatSykinhibitionwaseffectiveat inducingapoptosisofhumancGVHDBcells.Together, these data demonstrate a therapeutic potential of targeting B-cell Syk signaling in cGVHD.

AB - 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 humancGVHDBcells 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. Bonemarrow-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 CD80/861 dendritic cells. Inmultiple distinctmodels of sclerodermatouscGVHD, clinical and pathological diseasemanifestationswere not eliminated when mice were therapeutically treated with fostamatinib, though both clinical and immunologic effects could be observed in one of these sclerodermamodels. We furtherdemonstratedthatSykinhibitionwaseffectiveat inducingapoptosisofhumancGVHDBcells.Together, these data demonstrate a therapeutic potential of targeting B-cell Syk signaling in cGVHD.

UR - http://www.scopus.com/inward/record.url?scp=84933559790&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84933559790&partnerID=8YFLogxK

U2 - 10.1182/blood-2014-08-595470

DO - 10.1182/blood-2014-08-595470

M3 - Article

C2 - 25852057

AN - SCOPUS:84933559790

VL - 125

SP - 4085

EP - 4094

JO - Blood

JF - Blood

SN - 0006-4971

IS - 26

ER -