title: Blockade of interleukin-6 signaling suppresses experimental autoimmune uveoretinitis by the inhibition of inflammatory Th17 responses.
abstract: The aim of this study was to investigate the effect of anti-mouse IL-6 receptor monoclonal antibody (MR16-1) treatment on CD4 T cell differentiation and compared it to the effect of anti-TNF mAb treatment with using a murine model of experimental autoimmune uveoretinitis (EAU). C57BL/6 mice were immunized with interphotoreceptor retinoid-binding protein (IRBP) to induce ocular inflammation treatment with control IgG or MR16-1 or anti-TNF mAb. Helper T cells differentiation was analyzed during the development of EAU. Immunization with IRBP increased the frequency of Th17 cells rather than Th1 cells in the early stage of EAU. Treatment with MR16-1 on the same day as immunization (day 0) or one day after (day 1) suppressed ocular inflammation in EAU mice. Treatment with MR16-1 on day 0 inhibited the induction of Th17 cells in vivo, and inhibited not only IRBP-responsive Th17 cells but also their Th1 counterparts and induced IRBP-responsive regulatory T (Treg) cells in vitro. The administration of anti-TNF mAb had no significant protective effect in EAU mice. The protective effect of anti-IL-6R mAb treatment, but not anti-TNF mAb treatment on EAU correlated with the inhibition of Th17 differentiation. This finding suggests that IL-6 blockade may have a therapeutic effect on human ocular inflammation which is mediated via mechanisms distinct from those of TNF blockade. IL-6 blockade may thus represent an alternative therapy for patients with ocular inflammation who are refractory to anti-TNF mAb therapy.
authors.affiliation: Department of Ophthalmology, Osaka University Medical School, E7, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hohki
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Ohguro
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Haruta
authors.forename: Kei
authors.initials: K
authors.lastname: Nakai
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Terabe
authors.forename: Satoshi
authors.initials: S
authors.lastname: Serada
authors.forename: Minoru
authors.initials: M
authors.lastname: Fujimoto
authors.forename: Shintaro
authors.initials: S
authors.lastname: Nomura
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Kawahata
authors.forename: Tadamitsu
authors.initials: T
authors.lastname: Kishimoto
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Naka
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001327:Autoimmune Diseases / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005136:Eye Proteins; D005260:Female; D020381:Interleukin-17 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D019947:Receptors, Interleukin-6 / Q000276:immunology; D012173:Retinitis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D012177:Retinol-Binding Proteins; D015398:Signal Transduction / Q000187:drug effects*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D014605:Uveitis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D000099214:Retinol-Binding Proteins, Interstitial
chemical_list: D000911:Antibodies, Monoclonal; D005136:Eye Proteins; D020381:Interleukin-17; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D012177:Retinol-Binding Proteins; D014409:Tumor Necrosis Factor-alpha; D000099214:Retinol-Binding Proteins, Interstitial