Prevention of experimental autoimmune uveoretinitis by blockade of osteopontin with small interfering RNA
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概要
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Osteopontin (OPN) is elevated during the progression of experimental autoimmune uveoretinitis (EAU) in C57BL/6 (B6) mice. Furthermore, EAU symptoms are ameliorated in OPN knockout mice or in B6 mice treated with anti-OPN antibody (M5). Recently, OPN has been shown to promote the Th1 response not only in the extracellular space as a secretory protein but also in cytosol as a signaling component. Thus, we attempted to reduce OPN in both compartments by using a small interfering RNA (siRNA) targeting the OPN coding sequence (OPN-siRNA). EAU was induced in B6 mice by immunization with human interphotoreceptor retinoid-binding protein (hIRBP) peptide sequence 1-20. The OPN- or control-siRNA was administered with hydrodynamic methods 24 hours before and simultaneously with immunization (prevention regimen). When plasma OPN levels were quantified following siRNA administration with the prevention regimen, the level in the OPN-siRNA-treated group was significantly lower than that in the control-siRNA-treated group. Accordingly, the clinical and histopathological scores of EAU were significantly reduced in B6 mice when siRNA caused OPN blockade. Furthermore, TNF-α, IFN-γ, IL-2, GM-CSF and IL-17 levels in the culture supernatants were markedly suppressed in the OPN-siRNA-treated group, whereas the proliferative responses of T lymphocytes from regional lymph nodes against immunogenic peptides was not significantly reduced. On the other hand, the protection was not significant if the mice received the OPN-siRNA treatment on day 7 and day 8 after immunization when the clinical symptoms appeared overt (reversal regimen). Our results suggest that OPN blockade with OPN-siRNA can be an alternative choice for the usage of anti-OPN antibody and controlling uveoretinitis in the preventive regimen.
著者
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Uede Toshimitsu
Division Of Molecular Immunology Institute For Genetic Medicine Hokkaido University
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Kosakai Yoshio
Department Of Cardiovascldar Surgery National Cardiovascudar Center
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Ohno Shigeaki
北海道大学 大学院医学研究科感覚器病学講座眼科学分野
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Morimoto Junko
Fukuoka University Hospital Kidney Center
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Kadoshima Yoko
Department Of Public Health Kanazawa Medical University
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Kaneko Yoshihiro
The Second Department Of Internal Medicine Yokohama City University School Of Medicine
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Namba Kenichi
Department Of Ophthalmology And Visual Sciences Hokkaido University Graduate School Of Medicine
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Ohno Shigeaki
Department Of Ocular Inflammation And Immunology Hokkaido University Graduate School Of Medicine
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Ohno Shigeaki
Department Of Ophthalmology And Visual Sciences Hokkaido University Graduate School Of Medicine
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Kitaichi Nobuyoshi
Department Of Ophthalmology Hokkaido University Graduate School Of Medicine
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KITAMURA Mizuki
Department of Ophthalmology, Hokkaido University Graduate School of Medicine
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Kitamura Mizuki
Department Of Ophthalmology Hokkaido University Graduate School Of Medicine
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Namba Kenichi
Department Of Ophthalmology Hokkaido University Graduate School Of Medicine
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Kon Shigeyuki
Divison Of Molecular Immunology Institute For Genetic Medicine Hokkaido University
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Ohno S
Department Of Ocular Inflammation And Immunology Hokkaido University Graduate School Of Medicine
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Kitaichi Nobuyoshi
Department Of Ophthalmology Health Sciences University Of Hokkaido
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Kaibara Nobuaki
Department Of Ophthalmology Hokkaido University Graduate School Of Medicine
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