title: Collagen-induced arthritis: severity and immune response attenuation using multivalent N-acetyl glucosamine.
abstract: Rheumatoid arthritis is an autoimmunity leading to considerable impairment of quality of life. N-acetyl glucosamine (GlcNAc) has been described previously as a potent modulator of experimental arthritis in animal models and is used for osteoarthritis treatment in humans, praised for its lack of adverse effects. In this study we present a comprehensive immunological analysis of multivalent GlcNAc-terminated glycoconjugate (GC) application in the treatment of collagen-induced arthritis (CIA) and its clinical outcome. We used immunohistochemistry and FACS to describe conditions on the inflammation site. Systemic and clinical effects were evaluated by FACS, cytotoxicity assay, ELISA, cytometric bead array (CBA), RT-PCR and clinical scoring. We found reduced inflammatory infiltration, NKG2D expression on NK and suppression of T, B and antigen-presenting cells (APC) in the synovia. On the systemic level, GCs prevented the activation of monocyte- and B cell-derived APCs, the rise of TNF-α and IFN-γ levels, and subsequent type II collagen (CII)-specific IgG2a formation. Moreover, we detected an increase of anti-inflammatory IL-4 mRNA in the spleen. Similar to the synovia, the GCs caused a significant reduction of NKG2D-expressing NK cells in the spleen without influencing their lytic function. GCs effectively postponed the onset of arthritic symptoms, reduced their severity and in 18% (GN8P) and 31% (GN4C) of the cases completely prevented their appearance. Our data prove that GlcNAc glycoconjugates prevent the inflammatory response, involving proinflammatory cytokine rise, APC activation and NKG2D expression, leading to the attenuation of clinical symptoms. These results support the glycobiological approach to the treatment of collagen-induced arthritis/rheumatoid arthritis (CIA/RA) as a way of bringing new prospects for more effective therapeutic interventions.
authors.affiliation: Laboratory of Molecular Biology and Immunology, Institute of Microbiology, ASCR v.v.i., Prague, Czech Republic.
authors.forename: J
authors.initials: J
authors.lastname: Richter
authors.forename: K
authors.initials: K
authors.lastname: Capková
authors.forename: V
authors.initials: V
authors.lastname: Hříbalová
authors.forename: L
authors.initials: L
authors.lastname: Vannucci
authors.forename: I
authors.initials: I
authors.lastname: Danyi
authors.forename: M
authors.initials: M
authors.lastname: Malý
authors.forename: A
authors.initials: A
authors.lastname: Fišerová
mesh_terms: D000117:Acetylglucosamine / Q000008:administration & dosage*; D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects* / Q000276:immunology; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism; D013583:Synovial Membrane / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
chemical_list: D016207:Cytokines; C527086:Klrk1 protein, mouse; D055655:NK Cell Lectin-Like Receptor Subfamily K; D000117:Acetylglucosamine
keywords: CIA; GlcNAc glycoconjugates; clinical scoring; cytokines; humoral response