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* Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan;
Department of Ophthalmology and Visual Sciences, Hokkaido University Graduate School of Medicine, Sapporo, Japan;
Division of Molecular Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan;
Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854; and
¶ The Forsyth Institute, The Fenway, Boston, MA 02115
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 immunized 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-immunized OPN–/– mice exhibited reduced Ag-specific proliferation and proinflammatory cytokine (TNF-
and IFN-
) production 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 stimulation with hIRBP peptide in the presence of M5 Ab in the culture. Our present results demonstrate that OPN may represent a novel therapeutic target to control uveoretinitis.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by a grant for research on sensory and communicative disorders from the Ministry of Health, Labor, and Welfare, Japan; by Grants-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 Ministry of Education, Culture, Sports, Science, and Technology, Japan.
2 Address correspondence and reprint requests to Dr. Kazunori Onoé, Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo 060-0815, Japan. E-mail address: kazunori{at}igm.hokudai.ac.jp
3 Abbreviations used in this paper: EAU, experimental autoimmune uveoretinitis; hIRBP, human interphotoreceptor retinoid-binding protein; OPN, osteopontin; PTX, pertussis toxin; RGD, arginine-glycine-aspartic acid; WT, wild type.
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  M. J. Mattapallil, A. Sahin, P. B. Silver, S.-H. Sun, C.-C. Chan, E. F. Remmers, J. F. Hejtmancik, and R. R. Caspi Common Genetic Determinants of Uveitis Shared with Other Autoimmune Disorders J. Immunol., May 15, 2008; 180(10): 6751 - 6759. [Abstract] [Full Text] [PDF]
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