title: Gilt required for RTL550-CYS-MOG to treat experimental autoimmune encephalomyelitis.
abstract: MHC class II-derived recombinant T cell receptor ligands (RTLs) modulate the behavior of pathogenic T cells and can reverse clinical and histological signs of autoimmune disease in experimental autoimmune encephalomyelitis (EAE), experimental autoimmune uveitis (EAU) and collagen-induced arthritis (CIA), and are currently in clinical trials for treatment of multiple sclerosis (MS). To expand the utility of these rationally-designed biologics and explore their mechanism(s) of activity in vivo, we have engineered RTL constructs bearing cysteine-tethered antigenic peptides and demonstrate that the appropriate cysteine-tethered RTLs effectively treat EAE. The data presented here suggests that the mechanism by which antigen-specific tolerance induction by RTLs bearing cysteine-tethered antigenic peptides in vivo involves delivery of RTL/antigen to endosomal compartments for processing and re-presentation by full-length MHC class II, with RTLs bearing cysteine-tethered antigenic peptides requiring gamma-interferon-inducible lysosomal thiol-reductase (GILT) for therapeutic activity.
authors.affiliation: Department of Neurology, Oregon Health & Science University, Portland, 97239, USA. ggb@ohsu.edu
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Burrows
authors.forename: Roberto
authors.initials: R
authors.lastname: Meza-Romero
authors.forename: Jianya
authors.initials: J
authors.lastname: Huan
authors.forename: Sushmita
authors.initials: S
authors.lastname: Sinha
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Mooney
authors.forename: Arthur A
authors.initials: AA
authors.lastname: Vandenbark
authors.forename: Halina
authors.initials: H
authors.lastname: Offner
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy*; D011992:Endosomes / Q000737:chemistry / Q000378:metabolism; D005802:Genes, MHC Class II / Q000235:genetics; D000949:Histocompatibility Antigens Class II / Q000627:therapeutic use*; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009169:Mycobacterium tuberculosis / Q000276:immunology; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D050862:Oxidoreductases Acting on Sulfur Group Donors; D010446:Peptide Fragments / Q000627:therapeutic use*; D015202:Protein Engineering; D011994:Recombinant Proteins / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000378:metabolism
chemical_list: D000949:Histocompatibility Antigens Class II; D008024:Ligands; D010446:Peptide Fragments; D011994:Recombinant Proteins; C574733:cysteine-tethered MOG-35-55 recombinant I-Ab; D010088:Oxidoreductases; C483811:Ifi30 protein, mouse; D050862:Oxidoreductases Acting on Sulfur Group Donors