title: Targeted Rho-associated kinase 2 inhibition suppresses murine and human chronic GVHD through a Stat3-dependent mechanism.
abstract: Chronic graft-versus-host disease (cGVHD) remains a major complication following allogeneic bone marrow transplantation (BMT). The discovery of novel therapeutics is dependent on assessment in preclinical murine models of cGVHD. Rho-associated kinase 2 (ROCK2) recently was shown to be implicated in regulation of interleukin-21 (IL-21) and IL-17 secretion in mice and humans. Here, we report that the selective ROCK2 inhibitor KD025 effectively ameliorates cGVHD in multiple models: a full major histocompatibility complex (MHC) mismatch model of multiorgan system cGVHD with bronchiolitis obliterans syndrome and a minor MHC mismatch model of sclerodermatous GVHD. Treatment with KD025 resulted in normalization of pathogenic pulmonary function, which correlates with a marked reduction of antibody and collagen deposition in the lungs of treated mice to levels comparable to non-cGVHD controls. Spleens of mice treated with KD025 had decreased frequency of T follicular helper cells and increased frequency of T follicular regulatory cells, accompanied by a reduction in signal transducer and activator of transcription 3 (STAT3) and concurrent increase in STAT5 phosphorylation. The critical role of STAT3 in this cGVHD model was confirmed by data showing that mice transplanted with inducible STAT3-deficient T cells had pulmonary function comparable to the healthy negative controls. The therapeutic potential of targeted ROCK2 inhibition in the clinic was solidified further by human data demonstrating the KD025 inhibits the secretion of IL-21, IL-17, and interferon γ along with decreasing phosphorylated STAT3 and reduced protein expression of interferon regulatory factor 4 and B-cell lymphoma 6 (BCL6) in human peripheral blood mononuclear cells purified from active cGVHD patients. Together these data highlight the potential of targeted ROCK2 inhibition for clinical cGVHD therapy.
authors.affiliation: Division of Blood and Marrow Transplantation, Masonic Cancer Center and Department of Pediatrics, University of Minnesota, Minneapolis, MN;
authors.forename: Ryan
authors.initials: R
authors.lastname: Flynn
authors.affiliation: Division of Blood and Marrow Transplantation, Masonic Cancer Center and Department of Pediatrics, University of Minnesota, Minneapolis, MN;
authors.forename: Katelyn
authors.initials: K
authors.lastname: Paz
authors.affiliation: Division of Blood and Marrow Transplantation, Masonic Cancer Center and Department of Pediatrics, University of Minnesota, Minneapolis, MN;
authors.forename: Jing
authors.initials: J
authors.lastname: Du
authors.affiliation: Division of Blood and Marrow Transplantation, Masonic Cancer Center and Department of Pediatrics, University of Minnesota, Minneapolis, MN;
authors.forename: Dawn K
authors.initials: DK
authors.lastname: Reichenbach
authors.affiliation: Division of Blood and Marrow Transplantation, Masonic Cancer Center and Department of Pediatrics, University of Minnesota, Minneapolis, MN;
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Taylor
authors.affiliation: Division of Blood and Marrow Transplantation, Masonic Cancer Center and Department of Pediatrics, University of Minnesota, Minneapolis, MN;
authors.forename: Angela
authors.initials: A
authors.lastname: Panoskaltsis-Mortari
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center and Department of Oncology, The Johns Hopkins University, Baltimore, MD;
authors.forename: Ante
authors.initials: A
authors.lastname: Vulic
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center and Department of Oncology, The Johns Hopkins University, Baltimore, MD;
authors.forename: Leo
authors.initials: L
authors.lastname: Luznik
authors.affiliation: Department of Immunology, Queensland Institute of Medical Research, Brisbane, Australia;
authors.forename: Kelli K P
authors.initials: KK
authors.lastname: MacDonald
authors.affiliation: Department of Immunology, Queensland Institute of Medical Research, Brisbane, Australia;
authors.forename: Geoffrey R
authors.initials: GR
authors.lastname: Hill
authors.affiliation: Kadmon Research Institute, New York, NY;
authors.forename: Melanie S
authors.initials: MS
authors.lastname: Nyuydzefe
authors.affiliation: Kadmon Research Institute, New York, NY;
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Weiss
authors.affiliation: Kadmon Research Institute, New York, NY;
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Kadmon Research Institute, New York, NY;
authors.forename: Alissa
authors.initials: A
authors.lastname: Trzeciak
authors.affiliation: Lineberger Comprehensive Cancer Center Division of Hematology/Oncology, Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC;
authors.forename: Jon S
authors.initials: JS
authors.lastname: Serody
authors.affiliation: Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, CA;
authors.forename: Ethan G
authors.initials: EG
authors.lastname: Aguilar
authors.affiliation: Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, CA;
authors.forename: William J
authors.initials: WJ
authors.lastname: Murphy
authors.affiliation: Life Sciences Institute and Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI;
authors.forename: Ivan
authors.initials: I
authors.lastname: Maillard
authors.affiliation: Department of Pediatrics, Georgia Health Sciences University, Augusta, GA; and.
authors.forename: David
authors.initials: D
authors.lastname: Munn
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA.
authors.forename: John
authors.initials: J
authors.lastname: Koreth
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA.
authors.forename: Corey S
authors.initials: CS
authors.lastname: Cutler
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA.
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Antin
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA.
authors.forename: Jerome
authors.initials: J
authors.lastname: Ritz
authors.affiliation: Kadmon Research Institute, New York, NY;
authors.forename: Samuel D
authors.initials: SD
authors.lastname: Waksal
authors.affiliation: Kadmon Research Institute, New York, NY;
authors.forename: Alexandra
authors.initials: A
authors.lastname: Zanin-Zhorov
authors.affiliation: Division of Blood and Marrow Transplantation, Masonic Cancer Center and Department of Pediatrics, University of Minnesota, Minneapolis, MN;
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
mesh_terms: D000818:Animals; D001989:Bronchiolitis Obliterans / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D002908:Chronic Disease; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004353:Drug Evaluation, Preclinical; D006086:Graft vs Host Disease / Q000188:drug therapy / Q000201:enzymology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008168:Lung / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000096:biosynthesis / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000096:biosynthesis / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000172:deficiency / Q000502:physiology*; D013047:Specific Pathogen-Free Organisms; D013154:Spleen / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000473:pathology / Q000637:transplantation; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: C084103:BCL6 protein, human; C490010:Bcl6 protein, mouse; D016207:Cytokines; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D047428:Protein Kinase Inhibitors; D051560:Proto-Oncogene Proteins c-bcl-6; C539900:RORC protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; C515852:ROCK2 protein, human; C515855:Rock2 protein, mouse; D054460:rho-Associated Kinases