title: Immune responses of linear and cyclic PLP139-151 mutant peptides in SJL/J mice: peptides in their free state versus mannan conjugation.
abstract: BACKGROUND
  The predominant proteins of the CNS are myelin basic protein, proteolipid protein (PLP) and myelin oligodendrocyte glycoprotein. PLP139-151 is one of the major encephalitogenic epitopes of PLP. The epitope PLP139-151 binds to MHC class II (I-A(s)) of SJL/J mice and induces Th1 responses.
  
  
  OBJECTIVE
  The aim was to synthesize and test the immunological activity and cyclic analogs of PLP139-151 peptide and determine the immunological differences between adjuvant and conjugation to mannan. Materials & methods: We designed and synthesized cyclic peptides based on the linear PLP139-151 epitope by mutating critical T-cell receptor contact sites of residues W(144) and H(147), resulting in the mutant peptides PLP139-151, [L(144), R(147)]PLP139-151 or cyclo(139-151)PLP139-151 and cyclo(139-151) [L(144), R(147)]PLP139-151. In this study, mice were immunized with mutant peptides either emulsified in complete Freund's adjuvant or conjugated to reduced mannan and responses were assessed.
  
  
  RESULTS
  Linear double-mutant peptide [L(144), R(147)]PLP139-151 induced high levels of IL-4 responses and low levels of IgG total, and cyclization of this analog elicited low levels of IFN-γ. Moreover, linear [L(144), R(147)]PLP139-151 conjugated to reduced mannan did not induce IFN-γ, whilst both linear agonist PLP139-151 and cyclic agonist cyclo(139-151)PLP139-151 induced IFN-γ-secreting T cells. Molecular dynamics simulations of linear and cyclic(139-151)PLP139-151 analogs indicated the difference in topology of the most important for biological activity amino acids.
  
  
  CONCLUSIONS
  Cyclic double-mutant analog cyclo(139-151) [L(144), R(147)]PLP139-151 has potential for further studies for the immunotherapy of multiple sclerosis.
authors.affiliation: Burnet Institute, Centre for Immunology, Immunology & Vaccine Laboratory, Melbourne, VIC, Australia.
authors.forename: Maria
authors.initials: M
authors.lastname: Katsara
authors.forename: Spyros
authors.initials: S
authors.lastname: Deraos
authors.forename: Theodore V
authors.initials: TV
authors.lastname: Tselios
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Pietersz
authors.forename: John
authors.initials: J
authors.lastname: Matsoukas
authors.forename: Vasso
authors.initials: V
authors.lastname: Apostolopoulos
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D005260:Female; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects / Q000276:immunology*; D007114:Immunization; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism; D008351:Mannans / Q000737:chemistry / Q000276:immunology*; D008815:Mice, Inbred Strains; D009103:Multiple Sclerosis / Q000276:immunology; D009154:Mutation / Q000276:immunology; D018991:Myelin Proteolipid Protein / Q000235:genetics / Q000276:immunology; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: D000939:Epitopes; D007074:Immunoglobulin G; D008351:Mannans; D018991:Myelin Proteolipid Protein; D010446:Peptide Fragments; D010455:Peptides; D010456:Peptides, Cyclic; C435023:myelin proteolipid protein (139-151); D015847:Interleukin-4; D007371:Interferon-gamma
keywords: I-As; altered peptide ligand; autoimmunity; experimental autoimmune encephalomyelitis; multiple sclerosis; mutant analog; proteolipid protein