title: Protective effect of intravitreal administration of tresperimus, an immunosuppressive drug, on experimental autoimmune uveoretinitis.
abstract: OBJECTIVE
  To test the efficiency of locally administrated tresperimus in experimental autoimmune uveoretinitis (EAU).
  
  
  METHODS
  EAU was induced in Lewis rats by S-antigen (S-Ag) immunization. Three intravitreal injections of tresperimus (prevention or prevention/treatment protocols) were performed at different time points after immunization. The pharmacokinetics of tresperimus was evaluated in the ocular tissues and plasma. The in vitro effect of tresperimus was evaluated on macrophages. EAU was graded clinically and histologically. Blood ocular barrier permeability was evaluated by protein concentration in ocular fluids. Immune response to S-Ag was examined by delayed type hypersensitivity, the expression of inflammatory cytokines in lymph nodes, ocular fluids and serum by multiplex ELISA, and in ocular cells by RT-PCR.
  
  
  RESULTS
  In vitro, tresperimus significantly reduced the production of inflammatory cytokines by lipopolysaccharide-stimulated macrophages. In vivo, in the treatment protocol, efficient tresperimus levels were measured in the eye but not in the plasma up to 8 days after the last injection. Tresperimus efficiently reduced inflammation, retinal damage, and blood ocular barrier permeability breakdown. It inhibited nitric oxide synthase-2 and nuclear factor κBp65 expression in ocular macrophages. IL-2 and IL-17 were decreased in ocular media, while IL-18 was increased. By contrast, IL-2 and IL-17 levels were not modified in inguinal lymph nodes draining the immunization site. Moreover, cytokine levels in serum and delayed type hypersensitivity to S-Ag were not different in control and treated rats. In the prevention/treatment protocol, ocular immunosuppressive effects were also observed.
  
  
  CONCLUSIONS
  Locally administered tresperimus appears to be a potential immunosuppressive agent in the management of intraocular inflammation.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Paris, France. bousquetelodie29@gmail.com
authors.forename: Elodie
authors.initials: E
authors.lastname: Bousquet
authors.forename: Serge
authors.initials: S
authors.lastname: Camelo
authors.forename: Guillaume
authors.initials: G
authors.lastname: Leroux les Jardins
authors.forename: Brigitte
authors.initials: B
authors.lastname: Goldenberg
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Naud
authors.forename: Bernadette
authors.initials: B
authors.lastname: Besson-Lescure
authors.forename: Luc
authors.initials: L
authors.lastname: Lebreton
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Annat
authors.forename: Francine
authors.initials: F
authors.lastname: Behar-Cohen
authors.forename: Yvonne
authors.initials: Y
authors.lastname: de Kozak
mesh_terms: D000818:Animals; D001082:Aqueous Humor / Q000378:metabolism; D019393:Arrestin / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D001813:Blood-Retinal Barrier / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects; D002219:Carbamates / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D006968:Hypersensitivity, Delayed / Q000276:immunology; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D058449:Intravitreal Injections; D008198:Lymph Nodes / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D012313:RNA / Q000302:isolation & purification; D051381:Rats; D011917:Rats, Inbred Lew; D012173:Retinitis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014605:Uveitis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D014822:Vitreous Body / Q000378:metabolism
chemical_list: D019393:Arrestin; D002219:Carbamates; D016207:Cytokines; D007166:Immunosuppressive Agents; C092303:tresperimus; D012313:RNA