title: Altered peptide ligand modulation of experimental allergic encephalomyelitis: immune responses within the CNS.
abstract: An altered peptide ligand (analog) of the encephalitogenic epitope of proteolipid protein residues 139-151 (p139-151) in which residues 144 and 147 are substituted with leucine and arginine, respectively (LR), protects from clinical but not histological experimental allergic encephalomyelitis (EAE). To understand in situ events associated with this protection, T cells from brains of mice immunized with either native p139-151, the analog LR or a combination of the two were isolated and characterized. High proportions of cells from co-immunized mice (38%) and LR-immunized mice (58%) reacted to both p139-151 and LR, whereas fewer cells from p139-151 immunized mice (7%) were cross-reactive. T cell clones derived from brains of LR- and co-immunized mice were also cross-reactive in vitro. By reverse transcriptase-based polymerase chain reaction, higher levels of TGF-beta mRNA, and lower levels of TNF-alpha and IFN-gamma mRNA were found in the central nervous system (CNS) tissue of LR and co-immunized mice. Immunohistochemistry demonstrated greater TGF-beta immunoreactivity in CNS inflammatory foci in co-immunized and LR-immunized mice. There were no significant differences in CD4+ or CD8+ cell infiltrates among the groups and differences in other cytokines were not identified by immunocytochemistry. Protection from clinical EAE in LR and co-immunized mice was partially abolished by anti-TGF-beta antibody treatment. Thus, protection from clinical disease following immunization with the analog LR is associated with infiltration into the CNS of a T cell population that could potentially recognize the native PLP peptide and with enhanced TGF-beta production by cells within CNS inflammatory foci.
authors.affiliation: Biomedical Sciences Division, E. K. Shriver Center, Waltham, MA 02254, USA.
authors.forename: L
authors.initials: L
authors.lastname: Santambrogio
authors.forename: M B
authors.initials: MB
authors.lastname: Lees
authors.forename: R A
authors.initials: RA
authors.lastname: Sobel
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D001921:Brain / Q000276:immunology* / Q000473:pathology; D006224:Cricetinae; D003429:Cross Reactions; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D005260:Female; D007114:Immunization; D007124:Immunoenzyme Techniques; D007074:Immunoglobulin G / Q000276:immunology / Q000494:pharmacology; D007371:Interferon-gamma / Q000032:analysis; D008024:Ligands; D018655:Lymphocyte Count; D051379:Mice; D016297:Mutagenesis, Site-Directed; D018991:Myelin Proteolipid Protein / Q000737:chemistry / Q000276:immunology*; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology*; D016133:Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000037:antagonists & inhibitors; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: D000941:Antigens; D007074:Immunoglobulin G; D008024:Ligands; D018991:Myelin Proteolipid Protein; D010446:Peptide Fragments; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; C435023:myelin proteolipid protein (139-151); D007371:Interferon-gamma