title: Abrogation of collagen-induced arthritis by a peptidyl arginine deiminase inhibitor is associated with modulation of T cell-mediated immune responses.
abstract: Proteins containing citrulline, a post-translational modification of arginine, are generated by peptidyl arginine deiminases (PAD). Citrullinated proteins have pro-inflammatory effects in both innate and adaptive immune responses. Here, we examine the therapeutic effects in collagen-induced arthritis of the second generation PAD inhibitor, BB-Cl-amidine. Treatment after disease onset resulted in the reversal of clinical and histological changes of arthritis, associated with a marked reduction in citrullinated proteins in lymph nodes. There was little overall change in antibodies to collagen or antibodies to citrullinated peptides, but a shift from pro-inflammatory Th1 and Th17-type responses to pro-resolution Th2-type responses was demonstrated by serum cytokines and antibody subtypes. In lymph node cells from the arthritic mice treated with BB-Cl-amidine, there was a decrease in total cell numbers but an increase in the proportion of Th2 cells. BB-Cl-amidine had a pro-apoptotic effect on all Th subsets in vitro with Th17 cells appearing to be the most sensitive. We suggest that these immunoregulatory effects of PAD inhibition in CIA are complex, but primarily mediated by transcriptional regulation. We suggest that targeting PADs is a promising strategy for the treatment of chronic inflammatory disease.
authors.affiliation: Kennedy Institute, Nuffield Department of Orthopaedics, Rheumatology &Musculoskeletal Sciences, University of Oxford, Roosevelt Drive, Oxford OX3 7FY, UK.
authors.forename: Joanna
authors.initials: J
authors.lastname: Kawalkowska
authors.affiliation: Kennedy Institute, Nuffield Department of Orthopaedics, Rheumatology &Musculoskeletal Sciences, University of Oxford, Roosevelt Drive, Oxford OX3 7FY, UK.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Quirke
authors.affiliation: Laboratory of Cancer Biology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Ghari
authors.affiliation: Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7FZ, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Davis
authors.affiliation: Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, LRB 826, 364 Plantation Street, Worcester, MA, 01605, USA.
authors.forename: Venkataraman
authors.initials: V
authors.lastname: Subramanian
authors.affiliation: Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, LRB 826, 364 Plantation Street, Worcester, MA, 01605, USA.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Thompson
authors.affiliation: Kennedy Institute, Nuffield Department of Orthopaedics, Rheumatology &Musculoskeletal Sciences, University of Oxford, Roosevelt Drive, Oxford OX3 7FY, UK.
authors.forename: Richard O
authors.initials: RO
authors.lastname: Williams
authors.affiliation: Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7FZ, UK.
authors.forename: Roman
authors.initials: R
authors.lastname: Fischer
authors.affiliation: Laboratory of Cancer Biology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Nicholas B
authors.initials: NB
authors.lastname: La Thangue
authors.affiliation: Kennedy Institute, Nuffield Department of Orthopaedics, Rheumatology &Musculoskeletal Sciences, University of Oxford, Roosevelt Drive, Oxford OX3 7FY, UK.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Venables
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000276:immunology; D003094:Collagen; D016207:Cytokines / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D051379:Mice; D009952:Ornithine / Q000031:analogs & derivatives*; D000076342:Protein-Arginine Deiminases / Q000037:antagonists & inhibitors*; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology
chemical_list: D016207:Cytokines; D004791:Enzyme Inhibitors; D003094:Collagen; D009952:Ornithine; D000076342:Protein-Arginine Deiminases