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
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 124 Issue 11 Pg. 4867-76 (Nov 2014) ISSN: 1558-8238 [Electronic] United States
• PMID: 25271622 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Immunologic Factors
• Piperidines
• Pyrazoles
• Pyrimidines
• ibrutinib
• Adenine

Topics

• Adenine (analogs & derivatives)
• Animals
• Disease-Free Survival
• Drug Evaluation, Preclinical
• Graft vs Host Disease (drug therapy)
• Hematopoietic Stem Cell Transplantation (adverse effects)
• Immunologic Factors (pharmacology, therapeutic use)
• Lymphocyte Activation (drug effects)
• Mice, Inbred C57BL
• Piperidines
• Pyrazoles (pharmacology, therapeutic use)
• Pyrimidines (pharmacology, therapeutic use)