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 5

GC reactions and pulmonary immunoglobulin deposition are reduced with administration of ibrutinib.

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GC reactions and pulmonary immunoglobulin deposition are reduced with ad...
(A) GCs were imaged by staining 6-μm spleen sections with PNA conjugated to rhodamine (red) and DAPI (blue). (B) GC area (GC/mm2) was calculated from PNA-stained immunofluorescent images for each animal. The average area for each cohort is displayed. Error bars indicate SEM. (C) Splenocytes were purified from transplanted mice on day 60, and frequency of GC B cells was quantified. (D) 6-μm lung sections from day 60 transplanted mice were stained with anti-mouse Ig conjugated to FITC (green) and DAPI (blue) and (E) quantified with Adobe Photoshop CS3. Representative data from 3 independent experiments. *P < 0.05; ***P < 0.001. All measurements were conducted on day 60 after HSCT. Scale bars: 100 μm.