title: Controlling immune response and demyelination using highly potent bifunctional peptide inhibitors in the suppression of experimental autoimmune encephalomyelitis.
abstract: In this study, we investigated the efficacy of new bifunctional peptide inhibitors (BPIs) in suppressing experimental autoimmune encephalomyelitis (EAE) in an animal model. BPI [e.g. proteolipid protein-cyclo(1,8)-CPRGGSVC-NH2 (PLP-cIBR)] is a conjugate between the PLP139-151 peptide derived from proteolipid protein (PLP) and the cIBR7 peptide derived from domain-1 (D1) of intercellular adhesion molecule-1 (ICAM-1). PLP-cIBR is designed to bind to major histocompatibility complex (MHC)-II and leucocyte function-associated antigen-1 (LFA-1) simultaneously to inhibit the formation of the immunological synapse and alter the differentiation and activation of a subpopulation of T cells, thus inducing immunotolerance. The results show that PLP-cIBR is highly potent in ameliorating EAE, even at low concentrations and less frequent injections. Mice treated with PLP-cIBR had a higher secretion of cytokines related to regulatory and/or suppressor cells compared to phosphate-buffered saline (PBS)-treated mice. In contrast, T helper type 1 (Th1) cytokines were higher in mice treated with PBS compared to PLP-cIBR, suggesting that it suppressed Th1 proliferation. Also, we observed significantly less demyelination in PLP-cIBR-treated mice compared to the control, further indicating that PLP-cIBR promoted protection against demyelination.
authors.affiliation: Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, KS 66047, USA.
authors.forename: P
authors.initials: P
authors.lastname: Kiptoo
authors.forename: B
authors.initials: B
authors.lastname: Büyüktimkin
authors.forename: A H
authors.initials: AH
authors.lastname: Badawi
authors.forename: J
authors.initials: J
authors.lastname: Stewart
authors.forename: R
authors.initials: R
authors.lastname: Ridwan
authors.forename: T J
authors.initials: TJ
authors.lastname: Siahaan
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000941:Antigens / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology; D007108:Immune Tolerance / Q000187:drug effects; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000276:immunology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000235:genetics / Q000276:immunology; D051379:Mice; D008969:Molecular Sequence Data; D050506:Mutant Chimeric Proteins / Q000138:chemical synthesis / Q000276:immunology* / Q000494:pharmacology; D018991:Myelin Proteolipid Protein / Q000737:chemistry / Q000276:immunology*; D009186:Myelin Sheath / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000276:immunology* / Q000494:pharmacology; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology
chemical_list: D000941:Antigens; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D016169:Lymphocyte Function-Associated Antigen-1; D050506:Mutant Chimeric Proteins; D018991:Myelin Proteolipid Protein; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D018799:Intercellular Adhesion Molecule-1