title: Truncation of the neuritogenic peptide bP2(60-70) results in the generation of altered peptide ligands with the potential to interfere with T cell activation.
abstract: Due to the central role of T cells in the pathogenesis of inflammatory diseases of the peripheral nervous system like the Guillain-Barré syndrome, specific immunotherapies aim at modifying T cell responses. Use of truncated mutants of the neuritogenic peptide of myelin basic protein (MBP) has been shown to anergize autoreactive T cells and to reverse experimental autoimmune encephalitis (EAE). To establish a rationale basis for the use of altered peptide ligands (APLs) in the treatment of autoimmune diseases we designed a set of N- and C-terminally truncated mutants of the minimal experimental autoimmune neuritis (EAN) inducing bovine P2 (bP2) (60-70) peptide and compared them for the ability to induce immune responses and T cell receptor (TCR) cell signaling. Truncated peptides bound to MHC class II molecules and induced TCR internalization and expression of interferon gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) with decreasing potency. None of the shortened mutants elicited a proliferative response in P2-specific T cells. Stimulation of these antigen-specific T cells with peptide bP2(62-69) using antigen presenting cells (APCs) prepulsed with bP2(60-70) resulted in a significant decrease of the proliferative response. In agreement with the observed effects on T cell activation, analysis of TCR signaling demonstrated a lack of CD3 epsilon phosphorylation and MAPK activation. Moreover, repeated injection of bP2(62-69) significantly slowed progression of adoptive transfer EAN (AT-EAN). Taken together, these findings strongly suggest that peptide bP2(62-69) can favorably modulate the antigen-induced response of neuritogenic T cells.
authors.affiliation: Clinical Research Group for Multiple Sclerosis and Neuroimmunology, Department of Neurology, Julius-Maximilians-University, Würzburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Offenhäusser
authors.forename: Alexandra S
authors.initials: AS
authors.lastname: Herr
authors.forename: Jörg
authors.initials: J
authors.lastname: Hartkamp
authors.forename: Marca
authors.initials: M
authors.lastname: Wauben
authors.forename: Tim
authors.initials: T
authors.lastname: Magnus
authors.forename: Oliver
authors.initials: O
authors.lastname: Grauer
authors.forename: Silvia
authors.initials: S
authors.lastname: Seubert
authors.forename: Andreas
authors.initials: A
authors.lastname: Weishaupt
authors.forename: Klaus V
authors.initials: KV
authors.lastname: Toyka
authors.forename: Ralf
authors.initials: R
authors.lastname: Gold
authors.forename: Jakob
authors.initials: J
authors.lastname: Troppmair
mesh_terms: D000818:Animals; D020274:Autoimmune Diseases of the Nervous System / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000187:drug effects* / Q000276:immunology; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000187:drug effects / Q000276:immunology; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology; D008024:Ligands; D008970:Molecular Weight; D018996:Myelin P2 Protein / Q000737:chemistry* / Q000276:immunology / Q000494:pharmacology; D010446:Peptide Fragments / Q000737:chemistry* / Q000276:immunology / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects / Q000276:immunology; D017434:Protein Structure, Tertiary / Q000502:physiology; D051381:Rats; D011917:Rats, Inbred Lew; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
chemical_list: D000949:Histocompatibility Antigens Class II; D008024:Ligands; D018996:Myelin P2 Protein; D010446:Peptide Fragments