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Abrogation of Anti-Retinal Autoimmunity in IL-10 Transgenic Mice Due to Reduced T Cell Priming and Inhibition of Disease Effector Mechanisms¹

Rajeev K. Agarwal^2,*, Reiko Horai^2,*, Angelia M. Viley^*, Phyllis B. Silver^*, Rafael S. Grajewski^*, Shao Bo Su^*, Arrash T. Yazdani^*, Wei Zhu^*, Mitchell Kronenberg, Peter J. Murray, Robert L. Rutschman, Chi-Chao Chan^* and Rachel R. Caspi^3,*

^* The Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892; La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; and Department of Infectious Diseases, St. Jude Children’s Hospital, Memphis, TN 38105

Experimental autoimmune uveitis (EAU) induced by immunization of animals with retinal Ags is a model for human uveitis. The immunosuppressive cytokine IL-10 regulates EAU susceptibility and may be a factor in genetic resistance to EAU. To further elucidate the regulatory role of endogenous IL-10 in the mouse model of EAU, we examined transgenic (Tg) mice expressing IL-10 either in activated T cells (inducible) or in macrophages (constitutive). These IL-10-Tg mice and non-Tg wild-type controls were immunized with a uveitogenic regimen of the retinal Ag interphotoreceptor retinoid-binding protein. Constitutive expression of IL-10 in macrophages abrogated disease and reduced Ag-specific immunological responses. These mice had detectable levels of IL-10 in sera and in ocular extracts. In contrast, expression of IL-10 in activated T cells only partially protected from EAU and marginally reduced Ag-specific responses. All IL-10-Tg lines showed suppression of Ag-specific effector cytokines. APC from Tg mice constitutively expressing IL-10 in macrophages exhibited decreased ability to prime naive T cells, however, Ag presentation to already primed T cells was not compromised. Importantly, IL-10-Tg mice that received interphotoreceptor retinoid-binding protein-specific uveitogenic T cells from wild-type donors were protected from EAU. We suggest that constitutively produced endogenous IL-10 ameliorates the development of EAU by suppressing de novo priming of Ag-specific T cells and inhibiting the recruitment and/or function of inflammatory leukocytes, rather than by inhibiting local Ag presentation within the eye.

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 study was supported by National Institutes of Health intramural funding.

² R.K.A. and R.H. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Rachel R. Caspi, Laboratory of Immunology, NEI, National Institutes of Health, 10 Center Drive, 10/10N222, Bethesda, MD 20892. E-mail address: rcaspi{at}helix.nih.gov

⁴ Abbreviations used in this paper: EAU, experimental autoimmune uveitis; EAE, experimental autoimmune encephalomyelitis; Tg, transgenic; WT, wild type; IRBP, interphotoreceptor retinoid-binding protein; PTX, pertussis toxin; -MMP, -methyl-D-mannopyranoside; LN, lymph node; DTH, delayed-type hypersensitivity; PEC, peritoneal exudate cell.