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Autoimmune Uveoretinitis in Mice Osteopontin Aggravates Experimental Osteopontin Aggravates Experimental Autoimmune Uveoretinitis in Mice Mizuki Kitamura, Kazuya Iwabuchi, Nobuyoshi Kitaichi, Shigeyuki Kon, Hirokuni Kitamei, Kenichi Namba, This information is current as Kazuhiko Yoshida, David T. Denhardt, Susan R. Rittling, of September 28, 2021. Shigeaki Ohno, Toshimitsu Uede and Kazunori Onoé J Immunol 2007; 178:6567-6572; ; doi: 10.4049/jimmunol.178.10.6567 http://www.jimmunol.org/content/178/10/6567 Downloaded from References This article cites 50 articles, 26 of which you can access for free at: http://www.jimmunol.org/content/178/10/6567.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 28, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2007 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Osteopontin Aggravates Experimental Autoimmune Uveoretinitis in Mice1 Mizuki Kitamura,*† Kazuya Iwabuchi,* Nobuyoshi Kitaichi,† Shigeyuki Kon,‡ Hirokuni Kitamei,† Kenichi Namba,† Kazuhiko Yoshida,† David T. Denhardt,§ Susan R. Rittling,¶ Shigeaki Ohno,† Toshimitsu Uede,‡ and Kazunori Onoe´2* Human endogenous uveitis is a common sight-threatening intraocular inflammatory disease and has been studied extensively using a murine model of experimental autoimmune uveoretinitis (EAU). It is possibly mediated by Th1 immune responses. In the present study, we investigated the role of osteopontin (OPN), a protein with pleiotropic functions that contributes to the development of Th1 cell-mediated immunity. Accompanying EAU progression, OPN was elevated in wild-type (WT) mice that had been immu- nized with human interphotoreceptor retinoid-binding protein (hIRBP) peptide 1–20. OPN-deficient (OPN؊/؊) mice showed milder EAU progression in clinical and histopathological scores compared with those of WT mice. The T cells from hIRBP- Downloaded from -immunized OPN؊/؊ mice exhibited reduced Ag-specific proliferation and proinflammatory cytokine (TNF-␣ and IFN-␥) produc tion compared with those of WT T cells. When hIRBP-immunized WT mice were administered M5 Ab reacting to SLAYGLR sequence, a cryptic binding site to integrins within OPN, EAU development was significantly ameliorated. T cells from hIRBP- immunized WT mice showed significantly reduced proliferative responses and proinflammatory cytokine production upon stim- ulation with hIRBP peptide in the presence of M5 Ab in the culture. Our present results demonstrate that OPN may represent http://www.jimmunol.org/ a novel therapeutic target to control uveoretinitis. The Journal of Immunology, 2007, 178: 6567–6572. xperimental autoimmune uveoretinitis (EAU)3 is an an- Osteopontin (OPN), also known as early T lymphocyte activa- imal model of human endogenous uveitis, such as sym- tion 1 (Eta-1), is a secreted phosphoglycoprotein that contains the E pathetic ophthalmia, birdshot retinochoroidopathy, arginine-glycine-aspartic acid (RGD) integrin-binding sequence. Vogt-Koyanagi-Harada’s disease, and Behc¸et’s disease (1). The RGD sequence is also found in many extracellular matrix EAU is an organ-specific, T cell-mediated autoimmune disease proteins (8). OPN has been shown to mediate adhesion and mi- that can be induced by immunization with retinal Ag, e.g., hu- gration of a number of different cell types. It has been reported that man interphotoreceptor retinoid-binding protein or by the adop- ␣ ␤ ␣ ␤ ␣ ␤ ␣ ␤ ␣ ␤ ␣ ␤ by guest on September 28, 2021 the integrins v 1, v 3, v 5, 5 1, 8 1, and v 6 bind to OPN tive transfer of retinal Ag-specific T lymphocytes (2–4). EAU ␣ ␤ ␣ ␤ through RGD sequence and 4 1, 9 1 bind to non-RGD sites of is a Th1-dominant response. It has been demonstrated that the OPN (9). CD44 is known as one of the OPN receptors, and the augmentation of the Th2 response and T regulatory cytokine interaction of OPN with CD44 regulates macrophage migration production or down-regulation of the Th1 responses prevents and activation (10, 11). inflammatory responses and protects against the EAU develop- OPN is produced by a variety of inflammatory cells, including ment (5–7). T cells, macrophages, NK cells, and NKT cells (12, 13); induces IL-12 and IFN-␥ production; and inhibits IL-10 expression (14). Thus, OPN is considered to act as a cytokine that contributes to the *Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan; †Department of Ophthalmology and Visual Sciences, Hokkaido Uni- development of Th1-mediated immunity and diseases. Xu et al. versity Graduate School of Medicine, Sapporo, Japan; ‡Division of Molecular Im- (15) reported that CD44 was up-regulated in the eyes of EAU mice munology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan; §Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ and the disease severity was reduced by administration of anti- 08854; and ¶The Forsyth Institute, The Fenway, Boston, MA 02115 CD44 mAb. Of interest, OPN-positive cells were observed in the Received for publication October 19, 2006. Accepted for publication February ganglion cell layer of retinas in C57BL/6J mice (16). 22, 2007. Recent studies with OPN-deficient (OPNϪ/Ϫ) mice have dem- The costs of publication of this article were defrayed in part by the payment of page onstrated that OPN deficiency inhibits disease progression in some charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. experimental autoimmune models, such as experimental autoim- 1 This work was supported in part by a grant for research on sensory and communi- mune encephalomyelitis (17, 18) and anti-type II collagen Ab- cative disorders from the Ministry of Health, Labor, and Welfare, Japan; by Grants- induced arthritis (19). Furthermore, an Ab (M5) specific for in-Aid for Scientific Research (S) and (C) from Japan Society for the Promotion of Science; and a Grant-in-Aid for Scientific Research on Priority Areas from the Min- SLAYGLR sequence, which is newly exposed within OPN by istry of Education, Culture, Sports, Science, and Technology, Japan. thrombin cleavage, significantly suppressed a murine model of 2 Address correspondence and reprint requests to Dr. Kazunori Onoe´, Division of rheumatoid arthritis (20). Immunobiology, Institute for Genetic Medicine, Hokkaido University, Kita-15, In the present study, using a murine EAU model, we examined Nishi-7, Kita-ku, Sapporo 060-0815, Japan. E-mail address: kazunori@igm. hokudai.ac.jp the role of OPN in this organ-specific autoimmune disease. We Ϫ/Ϫ 3 Abbreviations used in this paper: EAU, experimental autoimmune uveoretinitis; demonstrate in this study that OPN mice develop significantly hIRBP, human interphotoreceptor retinoid-binding protein; OPN, osteopontin; milder EAU in comparison with that in wild-type (WT) controls. PTX, pertussis toxin; RGD, arginine-glycine-aspartic acid; WT, wild type. Furthermore, we will show that EAU is ameliorated by a single Copyright © 2007 by The American Association of Immunologists, Inc. 0022-1767/07/$2.00 administration of M5 Ab. www.jimmunol.org 6568 OPN IN EAU Materials and Methods Experimental animals Six- to 8-wk-old female C57BL/6 (H-2b) (WT) mice were obtained from Japan SLC. OPNϪ/Ϫ mice (21) were backcrossed 11 times to C57BL/6 mice at Institute for Genetic Medicine at Hokkaido University. These animals were maintained in a specific pathogen-free condition in the animal facility of Laboratory of Animal Experiment for Disease Model, Institute for Genetic Medicine at Hokkaido University. All studies were conducted in compliance with the Association for Research in Vision and Ophthalmology. Reagents Human interphotoreceptor retinoid-binding protein (hIRBP) peptide sequence 1–20 (GPTHLFQPSLVLDMAKVLLD) was purchased from Bordetella pertussis Sigma-Genosys. Purified toxin (PTX) was from FIGURE 1. Plasma OPN levels in EAU mice. C57BL/6 mice (n ϭ 24) Sigma-Aldrich, and CFA and Mycobacterium tuberculosis strain were immunized with hIRBP 1–20 (200 ␮g) emulsified in CFA (1:1 v/v) H37Ra were from Difco. containing 2.5 mg/ml M. tuberculosis. A total of 200 ␮l of the emulsion Immunization was injected s.c. Concurrent with immunization, 0.1 ␮g of PTX in 100 ␮l of PBS was injected i.p. as an additional adjuvant. Blood was collected To analyze the cell proliferative response, hIRBP 1–20 (100 ␮g) was emul- transcardially before immunization and on days 3, 7, 10, 14, 21, and 28 sified in CFA (1:1 v/v), and a total of 50 ␮l of the emulsion was injected s.c. (four mice/group). To induce EAU, hIRBP 1–20 (200 ␮g) was emul- after immunization. All blood samples were collected under EDTA, cen- Downloaded from Ϫ sified in CFA (1:1 v/v) containing 2.5 mg/ml M. tuberculosis. A total of trifuged to remove cells and debris, and stored at 80°C until used. Plasma 200 ␮l of the emulsion was injected s.c. Concurrent with immunization, 0.1 levels of OPN were measured by sandwich ELISA. ␮g of PTX in 100 ␮l of PBS was injected i.p. as an additional adjuvant (22). Evaluation of EAU ment (2 ␮g/ml insulin from bovine pancreas, 1.1 ␮g/ml iron-free Clinical assessment by funduscopic examination of the retinal inflamma- transferrin, 1 ng/ml sodium selenite, 100 ␮g/ml BSA, and 1 ␮g/ml linoleic tion was conducted every 3 or 4 days from day 7 after immunization (23) acid)) (Sigma-Aldrich).
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