title: 2-Chloroacetamidine, a novel immunomodulator, suppresses antigen-induced mouse airway inflammation.
abstract: BACKGROUND
  Citrullination is a presently under-recognized posttranslational protein modification catalyzed by PAD enzymes. Immune responses to citrullinated neo-epitopes are identified in a growing number of inflammatory and autoimmune diseases. However, the involvement of hypercitrullination in the pathogenesis of bronchial asthma is still unknown.
  
  
  METHODS
  As main experimental tool, we examined the effect of 2-chloroacetamidine (2CA), a PAD enzyme inhibitor, on OVA-immunized and airway-challenged BALB/c mice; a commonly used model of allergic airway inflammation. We also measured the effect of 2CA on ex vivo lymphocytes and cell lines.
  
  
  RESULTS
  In vivo, 2CA dramatically suppressed lung tissue hypercitrullination, inflammatory cell recruitment, and airway-Th2 cytokine secretion. 2CA also suppressed systemic OVA-specific and total IgE production dramatically, effectively preventing de novo and diminishing established disease without measurably impacting general immunocompetence. In vitro, 2CA markedly inhibited the proliferation of mouse and human T cells with cell cycle block and apoptosis during a limited, postactivation phase.
  
  
  CONCLUSIONS
  2CA acts as narrow-spectrum immunosuppressant that selectively targets lymphocyte populations involved in active inflammatory tissue lesions. If hypercitrullination is generated in patients with asthma, 2CA may represent a novel disease modulator for human asthmatics/allergic diseases.
authors.affiliation: The Hospital for Sick Children Research Institute, Neuroscience and Mental Health, University of Toronto, Toronto, ON, Canada.
authors.forename: Y
authors.initials: Y
authors.lastname: Maezawa
authors.affiliation: The Hospital for Sick Children Research Institute, Neuroscience and Mental Health, University of Toronto, Toronto, ON, Canada.
authors.forename: G
authors.initials: G
authors.lastname: Paltser
authors.affiliation: The Hospital for Sick Children Research Institute, Neuroscience and Mental Health, University of Toronto, Toronto, ON, Canada.
authors.forename: H
authors.initials: H
authors.lastname: Tsui
authors.affiliation: The Hospital for Sick Children Research Institute, Neuroscience and Mental Health, University of Toronto, Toronto, ON, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Cheung
authors.affiliation: The Hospital for Sick Children Research Institute, Neuroscience and Mental Health, University of Toronto, Toronto, ON, Canada.
authors.forename: P
authors.initials: P
authors.lastname: Wu
authors.affiliation: Department of Neurology and Center for Neuroimmunology, University of Alabama at Birmingham, Birmingham, AL, USA.|Birmingham VA Medical Center, Birmingham, AL, USA.
authors.forename: A P
authors.initials: AP
authors.lastname: Nicholas
authors.affiliation: The Hospital for Sick Children Research Institute, Neuroscience and Mental Health, University of Toronto, Toronto, ON, Canada.
authors.forename: H-M
authors.initials: HM
authors.lastname: Dosch
mesh_terms: D000578:Amidines / Q000494:pharmacology*; D000818:Animals; D000941:Antigens / Q000276:immunology*; D017209:Apoptosis / Q000187:drug effects; D001249:Asthma / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D004195:Disease Models, Animal; D018450:Disease Progression; D004789:Enzyme Activation; D015870:Gene Expression; D006801:Humans; D006867:Hydrolases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D007155:Immunologic Factors / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D000076342:Protein-Arginine Deiminases; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism
chemical_list: C509120:2-chloroacetamidine; D000578:Amidines; D000941:Antigens; D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D006867:Hydrolases; D000076342:Protein-Arginine Deiminases
keywords: T cell; animal model; asthma; protein citrullination