title: CTLA4-Ig suppresses development of experimental autoimmune uveitis in the induction and effector phases: Comparison with blockade of interleukin-6.
abstract: Recently, a number of biologics have been used in the treatment of autoimmune diseases. However, in the treatment of severe autoimmune uveitis, only TNF-alpha inhibitors are preferably used and the effect of other biologics such as interleukin-6 (IL-6) signaling blockade or cytotoxic T-lymphocyte antigen-4-immunoglobulin fusion protein (CTLA4-Ig) has not been well studied. Previously, we reported that IL-6 blockade effectively suppresses the development of experimental autoimmune uveitis (EAU), a mouse model for uveitis, by inhibiting Th17 cell development. In this study, we investigated the effect of CTLA4-Ig on EAU development and compared it with the effect of anti-IL-6 receptor monoclonal antibody (MR16-1). C57BL/6J mice were immunized with interphotoreceptor retinoid-binding protein (IRBP) and treated once with CTLA4-Ig or MR16-1. Both CTLA4-Ig and MR16-1 administered in the induction phase (the same day as immunization) significantly reduced the clinical and histopathological scores of EAU. Fluorescence-activated cell sorting studies using draining lymph node (LN) cells from EAU mice 10 days after immunization showed that CTLA4-Ig can suppress early T-helper cell activation. CTLA4-Ig administered in the effector phase of the disease (one week after immunization), when IRBP-reactive T cells have been primed, also significantly reduced the clinical and histopathological scores of EAU. In contrast, MR16-1 administered in the effector phase did not ameliorate EAU. To investigate the differences between these biologics in the effector phase, in vitro restimulation analysis of LN cells obtained from EAU mice one week after immunization was performed and revealed that CTLA4-Ig, but not MR16-1, added to culture media could inhibit the proliferation of IRBP-specific CD4(+) T cells which possessed capacities of producing IFN-gamma and/or IL-17. Collectively, CTLA4-Ig ameliorated EAU through preventing initial T-cell activation in the induction phase and suppressing proliferation of IRBP-specific T cells in the effector phase. Blockade of IL-6 signaling did not have such inhibitory effects after T-cell priming. CTLA4-Ig may have therapeutic effects on human chronic uveitis.
authors: Laboratory for Immune Signal, National Institute of Biomedical Innovation, 7-6-8 Saito-asagi, Ibaraki, Osaka 567-0085, Japan; Department of Ophthalmology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors: Chiharu
authors: C
authors: Iwahashi
authors: Laboratory for Immune Signal, National Institute of Biomedical Innovation, 7-6-8 Saito-asagi, Ibaraki, Osaka 567-0085, Japan. Electronic address: mfujimoto@nibio.go.jp.
authors: Minoru
authors: M
authors: Fujimoto
authors: Department of Animal Bioscience, Nagahama Institute of Bio-Science and Technology, 1266 Tamura-Cho, Nagahama, Shiga 526-0829, Japan.
authors: Shintaro
authors: S
authors: Nomura
authors: Laboratory for Immune Signal, National Institute of Biomedical Innovation, 7-6-8 Saito-asagi, Ibaraki, Osaka 567-0085, Japan.
authors: Satoshi
authors: S
authors: Serada
authors: Department of Ophthalmology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors: Kei
authors: K
authors: Nakai
authors: Department of Ophthalmology, Japan Community Health Care Organization, Osaka Hospital, 4-2-78 Fukushima, Fukushima-Ku, Osaka 553-0003, Japan.
authors: Nobuyuki
authors: N
authors: Ohguro
authors: Department of Ophthalmology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors: Kohji
authors: K
authors: Nishida
authors: Laboratory for Immune Signal, National Institute of Biomedical Innovation, 7-6-8 Saito-asagi, Ibaraki, Osaka 567-0085, Japan.
authors: Tetsuji
authors: T
authors: Naka
mesh_terms: D000069594:Abatacept / Q000494:pharmacology*; D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D001327:Autoimmune Diseases / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005136:Eye Proteins; D005260:Female; D005434:Flow Cytometry; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D008198:Lymph Nodes; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments; D019947:Receptors, Interleukin-6 / Q000276:immunology; D012177:Retinol-Binding Proteins; D014605:Uveitis / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control*; D000099214:Retinol-Binding Proteins, Interstitial; D000093242:Interleukin-6 Inhibitors; D015850:Interleukin-6
chemical_list: D000069594:Abatacept; D019138:Antibodies, Blocking; D005136:Eye Proteins; D007166:Immunosuppressive Agents; D007371:Interferon-gamma; D020381:Interleukin-17; D010446:Peptide Fragments; D019947:Receptors, Interleukin-6; D012177:Retinol-Binding Proteins; D000099214:Retinol-Binding Proteins, Interstitial; D000093242:Interleukin-6 Inhibitors; C577686:interleukin-6, mouse; D015850:Interleukin-6
keywords: Biologic; CTLA4; Cytokine; Experimental autoimmune uveitis; T cell; Uveitis