title: Specific HDAC6 inhibition by ACY-738 reduces SLE pathogenesis in NZB/W mice.
abstract: We sought to determine if a selective HDAC6 inhibitor (ACY-738) decreases disease in NZB/W mice. From 22 to 38weeks-of-age, mice were injected intraperitoneally with 5 or 20mg/kg of ACY-738, or vehicle control. Body weight and proteinuria were measured every 2weeks, while sera anti-dsDNA, Ig isotypes, and cytokine levels were measured every 4weeks. Kidney disease was determined by evaluation of sera, urine, immune complex deposition, and renal pathology. Flow cytometric analysis assessed thymic, splenic, bone marrow, and peripheral lymphocyte differentiation patterns. Our results showed HDAC6 inhibition decreased SLE disease by inhibiting immune complex-mediated glomerulonephritis, sera anti-dsDNA levels, and inflammatory cytokine production and increasing splenic Treg cells. Inhibition of HDAC6 increased the percentage of cells in the early-stage developmental fractions of both pro- and pre-B cells. These results suggest that specific HDAC6 inhibition may be able to decrease SLE disease by altering aberrant T and B cell differentiation.
authors.affiliation: Department of Biomedical Sciences & Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, United States.
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Regna
authors.affiliation: Department of Biomedical Sciences & Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, United States.
authors.forename: Miranda D
authors.initials: MD
authors.lastname: Vieson
authors.affiliation: Department of Biomedical Sciences & Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, United States.
authors.forename: Xin M
authors.initials: XM
authors.lastname: Luo
authors.affiliation: Department of Biomedical Sciences & Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, United States.
authors.forename: Cristen B
authors.initials: CB
authors.lastname: Chafin
authors.affiliation: Department of Biotechnology, American University of Ras Al Khaimah, United Arab Emirates.
authors.forename: Abdul Gafoor
authors.initials: AG
authors.lastname: Puthiyaveetil
authors.affiliation: Department of Biomedical Sciences & Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, United States.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Hammond
authors.affiliation: Wake Forest University Primate Center, Department of Pathology/Comparative Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, United States.
authors.forename: David L
authors.initials: DL
authors.lastname: Caudell
authors.affiliation: Acetylon Pharmaceuticals, Inc., 70 Fargo St., Boston, MA 02210, United States.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Jarpe
authors.affiliation: Department of Biomedical Sciences & Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, United States; Edward Via College of Osteopathic Medicine, Blacksburg, VA 24060, United States. Electronic address: chreilly@vt.edu.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Reilly
mesh_terms: D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000276:immunology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000201:enzymology* / Q000503:physiopathology; D051379:Mice; D008814:Mice, Inbred NZB; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D060888:Real-Time Polymerase Chain Reaction; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology
chemical_list: D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; C583720:N-hydroxy-2-(1-phenylcycloproylamino)pyrimidine-5-carboxamide; D011743:Pyrimidines; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases
keywords: B cells; HDAC; Systemic lupus erythematosus; T cells