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Hydrodynamic Vaccination with DNA Encoding an Immunologically Privileged Retinal Antigen Protects from Autoimmunity through Induction of Regulatory T Cells¹

Phyllis B. Silver^*, Rajeev K. Agarwal^*, Shao-Bo Su^*, Isabelle Suffia^*, Rafael S. Grajewski^*, Dror Luger^*, Chi-Chao Chan^*, Rashid M. Mahdi^*, John M. Nickerson and Rachel R. Caspi^2,*

^* Laboratory of Immunology, National Eye Institute, National Institutes of Health Bethesda, MD; and Department of Ophthalmology, Emory University, Atlanta, GA 30322

The eye is an immunologically privileged organ whose Ags serve as targets for experimental autoimmune uveitis (EAU), a model for human uveitis. We used a hydrodynamic i.v. injection of naked DNA to express the uveitogenic retinal Ag interphotoreceptor retinoid-binding protein (IRBP) in the periphery, thus revoking its immune-privileged status. IRBP was expressed in the liver within hours of administration of as little as 10 µg of IRBP-DNA. Vaccinated mice were highly protected from EAU induced by immunization with IRBP for at least 10 wk after vaccination. Protection was partial in a reversal protocol. Mechanistic studies revealed specific hyporesponsiveness to IRBP without immune deviation, no evidence for apoptosis either by the Fas- or Bcl-2-regulated (mitochondrial) pathway and apparent lack of dependence on CD8⁺ cells, IL-10, or TGF-. In contrast, depletion of CD25⁺ cells after vaccination and before challenge markedly abrogated protection. IRBP-specific CD4⁺CD25^high T cells could be cultured from vaccinated mice and transferred protection to unvaccinated, EAU-challenged recipients. In vitro characterization of these cells revealed that they are Ag specific, anergic, express FoxP3, CTLA-4, and glucocorticoid-induced TNFR, and suppress by contact. Thus, expression of IRBP in the periphery by DNA vaccination results in tolerance that acts at least in part through induction of IRBP-specific, FoxP3⁺CD4⁺CD25⁺ regulatory T cells. DNA vaccination may offer a new approach to Ag-specific therapy of uveitis.

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 by National Institutes of Health intramural funding.

² Address correspondence and reprint requests to Dr. Rachel R. Caspi, Laboratory of Immunology, National Eye Institute, National Institutes of Health, 10 Center Drive, 10/10N222, Bethesda, MD 20892-1857. E-mail address: rcaspi{at}helix.nih.gov

³ Abbreviations used in this paper: EAU, experimental autoimmune uveitis; IRBP, interphotoreceptor retinoid-binding protein; Tg, transgenic; T-reg, T regulatory cell; WT, wild type; LN, lymph node; PPD, purified protein derivative; GITR, glucocorticoid-induced TNFR.