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Ibrutinib treatment ameliorates murine chronic graft-versus-host disease. 2014
Jason A Dubovsky, and
Ryan Flynn, and
Jing Du, and
Bonnie K Harrington, and
Yiming Zhong, and
Benjamin Kaffenberger, and
Carrie Yang, and
William H Towns, and
Amy Lehman, and
Amy J Johnson, and
Natarajan Muthusamy, and
Steven M Devine, and
Samantha Jaglowski, and
Jonathan S Serody, and
William J Murphy, and
David H Munn, and
Leo Luznik, and
Geoffrey R Hill, and
Henry K Wong, and
Kelli K P MacDonald, and
Ivan Maillard, and
John Koreth, and
Laurence Elias, and
Corey Cutler, and
Robert J Soiffer, and
Joseph H Antin, and
Jerome Ritz, and
Angela Panoskaltsis-Mortari, and
John C Byrd, and
Bruce R Blazar
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. CD4+ 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-2 inducible T cell kinase (ITK) that targets Th2 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 2 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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