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Coadministration of Plasmid DNA Constructs Encoding an Encephalitogenic Determinant and IL-10 Elicits Regulatory T Cell-Mediated Protective Immunity in the Central Nervous System¹

Department of Immunology, Bruce Rappaport Faculty of Medicine and Rappaport Family Institute for Research in the Medical Sciences, Haifa, Israel

We have previously shown that Ag-specific IL-10-producing regulatory T cells (Tr1) participate in the regulation of experimental autoimmune encephalomyelitis and that their specificity undergoes determinant spread in a reciprocal manner to effector T cell specificity. The current study shows that coadministration of plasmid DNA vaccines encoding IL-10 together with a plasmid encoding a myelin basic protein (MBP) encephalitogenic determinant during an ongoing disease rapidly amplifies this Tr1-mediated response, in a disease-specific manner. Thus, coadministration of both plasmids, but not the plasmid DNA encoding MBP alone, rapidly suppresses an ongoing disease. Tolerance included elevation in Ag-specific T cells producing IL-10 and an increase in apoptosis of cells around high endothelial venules in the CNS after successful therapy. Tolerance could be transferred by MBP-specific primary T cells isolated from protected donors and reversed by neutralizing Abs to IL-10 but not to IL-4. Due to the nature of determinant spread in this model, we could bring about evidence implying that rapid and effective induction of Tr1-induced active tolerance is dependent on redirecting the Tr1 response to the epitope to which the effector function dominates the response at a given time. The consequences of these findings to multiple sclerosis, and possibly other inflammatory autoimmune diseases are discussed.

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 grants from the Israel Science Academy, the Ministry of Health Chief Scientist, and the Rappaport Institute.

² Address correspondence and reprint requests to Dr. Nathan Karin, Rappaport Family Institute for Research in the Medical Sciences, P.O. Box 9697, Haifa 31096, Israel. E-mail address: nkarin{at}tx.technion.ac.il

³ Abbreviations used in this paper: EAE, experimental autoimmune encephalomyelitis; MS, multiple sclerosis; Tr1, regulatory T cell; MBP, myelin basic protein; EAN, experimental autoimmune neuritis; HEV, high endothelial venule.