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

Ibrutinib treatment ameliorates murine chronic graft-versus-host disease

Abstract

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.

Authors

Jason A. Dubovsky, Ryan Flynn, Jing Du, Bonnie K. Harrington, Yiming Zhong, Benjamin Kaffenberger, Carrie Yang, William H. Towns, Amy Lehman, Amy J. Johnson, Natarajan Muthusamy, Steven M. Devine, Samantha Jaglowski, Jonathan S. Serody, William J. Murphy, David H. Munn, Leo Luznik, Geoffrey R. Hill, Henry K. Wong, Kelli K.P. MacDonald, Ivan Maillard, John Koreth, Laurence Elias, Corey Cutler, Robert J. Soiffer, Joseph H. Antin, Jerome Ritz, Angela Panoskaltsis-Mortari, John C. Byrd, Bruce R. Blazar

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Figure 6

Development of BO is dependent on ITK expression in donor mature T cells.

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Development of BO is dependent on ITK expression in donor mature T cells...
(A) Day 60 PFTs from mice transplanted with WT BM and low numbers of either WT T cells or ITK-deficient T cells. (B) Pathologic scores in lung and (C) liver of day 60 transplanted mice. n = 5 mice/group in 2 independent experiments. *P < 0.05; **P < 0.01; ***P < 0.001.