Tolerance induction and autoimmune encephalomyelitis amelioration after administration of myelin basic protein-derived peptide.
Experimental autoimmune encephalomyelitis (EAE), a demyelinating disease of the central nervous system, is an animal model of paralyzing human disease, multiple sclerosis. EAE is readily induced by immunization with myelin basic protein (MBP) in mice transgenic for an alphabeta T cell receptor (TCR) that is specific for MBP. Subcutaneous injection of p17 (a peptide consisting of 17 NH2-terminal aminoacids of MBP) in complete Freund's adjuvant (CFA) causes paralysis. Induction of paralysis is inhibited by prior intraperitoneal injection of the same peptide in incomplete Freund's adjuvant (IFA). In addition, ongoing paralysis is ameliorated by subsequent intraperitoneal injection of p17 in IFA. Tolerance induction is equally efficient in Fas-deficient and IL-4-deficient TCR-transgenic mice, suggesting that neither activation-induced cell death nor differentiation into Th2 type cells plays a role in the tolerance induction. Tolerance induction by p17 seems to be based on reduction in the responsiveness of anti-MBP T cells, as documented by lower overall antigen-induced lymphokine production and proliferation, as well as diminished upregulation of early activation marker CD69 by tolerized T cells. We propose that continuous encounters of MBP-specific T cells with p17 play a critical role in the induction and maintenance of tolerance.
Marusić
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Howard Hughes Medical Institute, Center for Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Tonegawa
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D000818:Animals; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000517:prevention & control*; D007108:Immune Tolerance; D051379:Mice; D008822:Mice, Transgenic; D004676:Myelin Basic Protein / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
D004676:Myelin Basic Protein; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell