title: 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.forename: Jason A
authors.initials: JA
authors.lastname: Dubovsky
authors.forename: Ryan
authors.initials: R
authors.lastname: Flynn
authors.forename: Jing
authors.initials: J
authors.lastname: Du
authors.forename: Bonnie K
authors.initials: BK
authors.lastname: Harrington
authors.forename: Yiming
authors.initials: Y
authors.lastname: Zhong
authors.forename: Benjamin
authors.initials: B
authors.lastname: Kaffenberger
authors.forename: Carrie
authors.initials: C
authors.lastname: Yang
authors.forename: William H
authors.initials: WH
authors.lastname: Towns
authors.forename: Amy
authors.initials: A
authors.lastname: Lehman
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Johnson
authors.forename: Natarajan
authors.initials: N
authors.lastname: Muthusamy
authors.forename: Steven M
authors.initials: SM
authors.lastname: Devine
authors.forename: Samantha
authors.initials: S
authors.lastname: Jaglowski
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Serody
authors.forename: William J
authors.initials: WJ
authors.lastname: Murphy
authors.forename: David H
authors.initials: DH
authors.lastname: Munn
authors.forename: Leo
authors.initials: L
authors.lastname: Luznik
authors.forename: Geoffrey R
authors.initials: GR
authors.lastname: Hill
authors.forename: Henry K
authors.initials: HK
authors.lastname: Wong
authors.forename: Kelli K P
authors.initials: KK
authors.lastname: MacDonald
authors.forename: Ivan
authors.initials: I
authors.lastname: Maillard
authors.forename: John
authors.initials: J
authors.lastname: Koreth
authors.forename: Laurence
authors.initials: L
authors.lastname: Elias
authors.forename: Corey
authors.initials: C
authors.lastname: Cutler
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Soiffer
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Antin
authors.forename: Jerome
authors.initials: J
authors.lastname: Ritz
authors.forename: Angela
authors.initials: A
authors.lastname: Panoskaltsis-Mortari
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000818:Animals; D018572:Disease-Free Survival; D004353:Drug Evaluation, Preclinical; D006086:Graft vs Host Disease / Q000188:drug therapy*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D007155:Immunologic Factors / Q000494:pharmacology* / Q000627:therapeutic use; D008213:Lymphocyte Activation / Q000187:drug effects; D008810:Mice, Inbred C57BL; D010880:Piperidines; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D007155:Immunologic Factors; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D000225:Adenine