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.

• Klíčová slova
• CIA, GlcNAc glycoconjugates, clinical scoring, cytokines, humoral response,
• MeSH
• acetylglukosamin aplikace a dávkování   MeSH
• antigen prezentující buňky účinky léků   imunologie   MeSH
• artritida experimentální farmakoterapie   imunologie   MeSH
• B-lymfocyty účinky léků   imunologie   MeSH
• buněčná diferenciace účinky léků   MeSH
• buňky NK účinky léků   imunologie   MeSH
• cytokiny metabolismus   MeSH
• kultivované buňky MeSH
• lektinové receptory NK-buněk - podrodina K metabolismus   MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední DBA MeSH
• myši MeSH
• revmatoidní artritida farmakoterapie   imunologie   MeSH
• synoviální membrána účinky léků   imunologie   MeSH
• T-lymfocyty účinky léků   imunologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• acetylglukosamin MeSH
• cytokiny MeSH
• Klrk1 protein, mouse MeSH Prohlížeč
• lektinové receptory NK-buněk - podrodina K MeSH

N-Acetyl-D-glucosamine-substituted glycoconjugates (GCJs) with the polyamidoamine (GN8P) or calix[4]arene (GN4C) scaffold represent ligands for NKR-P1 molecule and induce NK cell-mediated cytotoxicity in vitro. The in vivo effect of these GCJs on mouse melanoma model was determined when administered either alone or in combination with non-specific immunostimulator keyhole limpet hemocyanin (KLH). All types of treatment significantly reduced the tumor growth on day 23, while GN4C as well as KLH were effective continuously (from day 14). The GN4C also induced the longest mean survival time (46.3 ± 11.1 d), followed by KLH+GN4C (36.4 ± 12.1), KLH (35.6 ± 6.5), KLH+GN8P (35.6 ± 6.7), and GN8P (32.4 ± 7.0), compared to controls (29.8 ± 3.6). The B16F10 specific cytotoxicity of peripheral blood cells was significantly elevated by both KLH and GN8P, whereas not by GN4C. KLH increased the effect of the GN4C, but did not influence that of GN8P. GN4C was proved to exert anticancer activity in mouse melanoma model. The combination of KLH with GCJs did not generate synergism.

• MeSH
• acetylglukosamin chemie   MeSH
• adjuvancia imunologická terapeutické užití   MeSH
• glykokonjugáty chemie   terapeutické užití   MeSH
• hemokyanin terapeutické užití   MeSH
• kombinovaná farmakoterapie MeSH
• lidé MeSH
• melanom farmakoterapie   patologie   MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory kůže farmakoterapie   patologie   MeSH
• protinádorové látky terapeutické užití   MeSH
• synergismus léků MeSH
• výsledek terapie MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• acetylglukosamin MeSH
• adjuvancia imunologická MeSH
• glykokonjugáty MeSH
• hemokyanin MeSH
• keyhole-limpet hemocyanin MeSH Prohlížeč
• protinádorové látky MeSH