title: A promising therapeutic approach for multiple sclerosis: recombinant T-cell receptor ligands modulate experimental autoimmune encephalomyelitis by reducing interleukin-17 production and inhibiting migration of encephalitogenic cells into the CNS.
abstract: Recombinant T-cell receptor ligands (RTLs) can prevent and reverse clinical and histological signs of experimental autoimmune encephalomyelitis (EAE) in an antigen-specific manner and are currently in clinical trials for treatment of subjects with multiple sclerosis (MS). To evaluate regulatory mechanisms, we designed and tested RTL551, containing the alpha1 and beta1 domains of the I-A(b) class II molecule covalently linked to the encephalitogenic MOG-35-55 peptide in C57BL/6 mice. Treatment of active or passive EAE with RTL551 after disease onset significantly reduced clinical signs and spinal cord lesions. Moreover, RTL551 treatment strongly and selectively reduced secretion of interleukin-17 and tumor necrosis factor alpha by transferred green fluorescent protein-positive (GFP+) MOG-35-55-reactive T-cells and almost completely abrogated existent GFP+ cellular infiltrates in affected spinal cord sections. Reduced inflammation in spinal cords of RTL551-treated mice was accompanied by a highly significant downregulation of chemokines and their receptors and inhibition of VCAM-1 (vascular cell adhesion molecule-1) and ICAM-1 (intercellular adhesion molecule-1) expression by endothelial cells. Thus, RTL therapy cannot only inhibit systemic production of encephalitogenic cytokines by the targeted myelin oligodendrocyte glycoprotein-reactive T-cells but also impedes downstream local recruitment and retention of inflammatory cells in the CNS. These findings indicate that targeted immunotherapy of antigen-specific T-cells can result in a reversal of CNS lesion formation and lend strong support to the application of the RTL approach for therapy in MS.
authors.affiliation: Neuroimmunology Research, Veterans Affairs Medical Center, Portland, Oregon 97239, USA.
authors.forename: Sushmita
authors.initials: S
authors.lastname: Sinha
authors.forename: Sandhya
authors.initials: S
authors.lastname: Subramanian
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Proctor
authors.forename: Laurie J
authors.initials: LJ
authors.lastname: Kaler
authors.forename: Marjorie
authors.initials: M
authors.lastname: Grafe
authors.forename: Rony
authors.initials: R
authors.lastname: Dahan
authors.forename: Jianya
authors.initials: J
authors.lastname: Huan
authors.forename: Arthur A
authors.initials: AA
authors.lastname: Vandenbark
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Burrows
authors.forename: Halina
authors.initials: H
authors.lastname: Offner
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000187:drug effects / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects* / Q000276:immunology; D018925:Chemokines / Q000187:drug effects / Q000276:immunology; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D049452:Green Fluorescent Proteins; D007155:Immunologic Factors / Q000494:pharmacology* / Q000627:therapeutic use; D007167:Immunotherapy / Q000379:methods; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism*; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology; D010446:Peptide Fragments / Q000494:pharmacology / Q000627:therapeutic use; D011948:Receptors, Antigen, T-Cell / Q000187:drug effects* / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000494:pharmacology* / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000276:immunology
chemical_list: D015815:Cell Adhesion Molecules; D018925:Chemokines; D007155:Immunologic Factors; D020381:Interleukin-17; D008024:Ligands; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D049452:Green Fluorescent Proteins