TY - JOUR
T1 - Ibrutinib treatment ameliorates murine chronic graft-versus-host disease
AU - Dubovsky, Jason A.
AU - Flynn, Ryan
AU - Du, Jing
AU - Harrington, Bonnie K.
AU - Zhong, Yiming
AU - Kaffenberger, Benjamin
AU - Yang, Carrie
AU - Towns, William H.
AU - Lehman, Amy
AU - Johnson, Amy J.
AU - Muthusamy, Natarajan
AU - Devine, Steven M.
AU - Jaglowski, Samantha
AU - Serody, Jonathan S.
AU - Murphy, William J.
AU - Munn, David H.
AU - Luznik, Leo
AU - Hill, Geoffrey R.
AU - Wong, Henry K.
AU - MacDonald, Kelli K P
AU - Maillard, Ivan
AU - Koreth, John
AU - Elias, Laurence
AU - Cutler, Corey
AU - Soiffer, Robert J.
AU - Antin, Joseph H.
AU - Ritz, Jerome
AU - Panoskaltsis-Mortari, Angela
AU - Byrd, John C.
AU - Blazar, Bruce R.
PY - 2014/11/3
Y1 - 2014/11/3
N2 - Chronic graft-versus-host disease (cGVHD) is a life-threatening impediment to allogeneic hematopoietic stem cell transplantation, and current therapies do not completely prevent and/or treat cGVHD. CD+ T cells and B cells mediate cGVHD; therefore, targeting these populations may inhibit cGVHD pathogenesis. Ibrutinib is an FDA-approved irreversible inhibitor of Bruton's tyrosine kinase (BTK) and IL- inducible T cell kinase (ITK) that targets Th cells and B cells and produces durable remissions in B cell malignancies with minimal toxicity. Here, we evaluated whether ibrutinib could reverse established cGVHD in complementary murine models, a model interrogating T cell-driven sclerodermatous cGVHD and an alloantibody-driven multiorgan system cGVHD model that induces bronchiolar obliterans (BO). In the T cell-mediated sclerodermatous cGVHD model, ibrutinib treatment delayed progression, improved survival, and ameliorated clinical and pathological manifestations. In the alloantibody-driven cGVHD model, ibrutinib treatment restored pulmonary function and reduced germinal center reactions and tissue immunoglobulin deposition. Animals lacking BTK and ITK did not develop cGVHD, indicating that these molecules are critical to cGVHD development. Furthermore, ibrutinib treatment reduced activation of T and B cells from patients with active cGVHD. Our data demonstrate that B cells and T cells drive cGVHD and suggest that ibrutinib has potential as a therapeutic agent, warranting consideration for cGVHD clinical trials.
AB - Chronic graft-versus-host disease (cGVHD) is a life-threatening impediment to allogeneic hematopoietic stem cell transplantation, and current therapies do not completely prevent and/or treat cGVHD. CD+ T cells and B cells mediate cGVHD; therefore, targeting these populations may inhibit cGVHD pathogenesis. Ibrutinib is an FDA-approved irreversible inhibitor of Bruton's tyrosine kinase (BTK) and IL- inducible T cell kinase (ITK) that targets Th cells and B cells and produces durable remissions in B cell malignancies with minimal toxicity. Here, we evaluated whether ibrutinib could reverse established cGVHD in complementary murine models, a model interrogating T cell-driven sclerodermatous cGVHD and an alloantibody-driven multiorgan system cGVHD model that induces bronchiolar obliterans (BO). In the T cell-mediated sclerodermatous cGVHD model, ibrutinib treatment delayed progression, improved survival, and ameliorated clinical and pathological manifestations. In the alloantibody-driven cGVHD model, ibrutinib treatment restored pulmonary function and reduced germinal center reactions and tissue immunoglobulin deposition. Animals lacking BTK and ITK did not develop cGVHD, indicating that these molecules are critical to cGVHD development. Furthermore, ibrutinib treatment reduced activation of T and B cells from patients with active cGVHD. Our data demonstrate that B cells and T cells drive cGVHD and suggest that ibrutinib has potential as a therapeutic agent, warranting consideration for cGVHD clinical trials.
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U2 - 10.1172/JCI75328
DO - 10.1172/JCI75328
M3 - Article
C2 - 25271622
AN - SCOPUS:84908656083
SN - 0021-9738
VL - 124
SP - 4867
EP - 4876
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 11
ER -