Coadministration of plasmid DNA constructs encoding an encephalitogenic determinant and IL-10 elicits regulatory T cell-mediated protective immunity in the central nervous system.
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.
Schif-Zuck
Sagie
S
Department of Immunology, Bruce Rappaport Faculty of Medicine and Rappaport Family Institute for Research in the Medical Sciences, Haifa 31096, Israel.
Wildbaum
Gizi
G
Karin
Nathan
N
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D015153:Blotting, Western; D002490:Central Nervous System / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000517:prevention & control; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D007108:Immune Tolerance; D007150:Immunohistochemistry; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology*; D004676:Myelin Basic Protein / Q000235:genetics / Q000276:immunology*; D010957:Plasmids / Q000235:genetics / Q000276:immunology; D051381:Rats; D011917:Rats, Inbred Lew; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D019444:Vaccines, DNA / Q000276:immunology*
D018984:Epitopes, T-Lymphocyte; D004676:Myelin Basic Protein; D019444:Vaccines, DNA; D016753:Interleukin-10