The C-type lectin-like receptors include the Nkrp1 protein family that regulates the activity of natural killer (NK) cells. Rat Nkrp1a was reported to bind monosaccharide moieties in a Ca2+-dependent manner in preference order of GalNac > GlcNAc >> Fuc >> Gal > Man. These findings established for rat Nkrp1a have been extrapolated to all additional Nkrp1 receptors and have been supported by numerous studies over the past two decades. However, since 1996 there has been controversy and another article showed lack of interactions with saccharides in 1999. Nevertheless, several high affinity saccharide ligands were synthesized in order to utilize their potential in antitumor therapy. Subsequently, protein ligands were introduced as specific binders for Nkrp1 proteins and three dimensional models of receptor/protein ligand interaction were derived from crystallographic data. Finally, for at least some members of the NK cell C-type lectin-like proteins, the "sweet story" was impaired by two reports in recent years. It has been shown that the rat Nkrp1a and CD69 do not bind saccharide ligands such as GlcNAc, GalNAc, chitotetraose and saccharide derivatives (GlcNAc-PAMAM) do not directly and specifically influence cytotoxic activity of NK cells as it was previously described.

• MeSH
• Killer Cells, Natural * chemistry   immunology   metabolism   MeSH
• Antigens, CD * chemistry   immunology   metabolism   MeSH
• Antigens, Differentiation, T-Lymphocyte * chemistry   immunology   metabolism   MeSH
• Rats MeSH
• NK Cell Lectin-Like Receptor Subfamily B * chemistry   immunology   metabolism   MeSH
• Lectins, C-Type * chemistry   immunology   metabolism   MeSH
• Humans MeSH
• Oligosaccharides * chemistry   immunology   metabolism   MeSH
• Protein Structure, Tertiary MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Antigens, CD * MeSH
• CD69 antigen MeSH Browser
• Antigens, Differentiation, T-Lymphocyte * MeSH
• KLRB1 protein, human MeSH Browser
• NK Cell Lectin-Like Receptor Subfamily B * MeSH
• Lectins, C-Type * MeSH
• Oligosaccharides * MeSH

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.

• Keywords
• CIA, GlcNAc glycoconjugates, clinical scoring, cytokines, humoral response,
• MeSH
• Acetylglucosamine administration & dosage   MeSH
• Antigen-Presenting Cells drug effects   immunology   MeSH
• Arthritis, Experimental drug therapy   immunology   MeSH
• B-Lymphocytes drug effects   immunology   MeSH
• Cell Differentiation drug effects   MeSH
• Killer Cells, Natural drug effects   immunology   MeSH
• Cytokines metabolism   MeSH
• Cells, Cultured MeSH
• NK Cell Lectin-Like Receptor Subfamily K metabolism   MeSH
• Humans MeSH
• Disease Models, Animal MeSH
• Mice, Inbred DBA MeSH
• Mice MeSH
• Arthritis, Rheumatoid drug therapy   immunology   MeSH
• Synovial Membrane drug effects   immunology   MeSH
• T-Lymphocytes drug effects   immunology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Acetylglucosamine MeSH
• Cytokines MeSH
• Klrk1 protein, mouse MeSH Browser
• NK Cell Lectin-Like Receptor Subfamily 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
• Acetylglucosamine chemistry   MeSH
• Adjuvants, Immunologic therapeutic use   MeSH
• Glycoconjugates chemistry   therapeutic use   MeSH
• Hemocyanins therapeutic use   MeSH
• Drug Therapy, Combination MeSH
• Humans MeSH
• Melanoma drug therapy   pathology   MeSH
• Disease Models, Animal MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Skin Neoplasms drug therapy   pathology   MeSH
• Antineoplastic Agents therapeutic use   MeSH
• Drug Synergism MeSH
• Treatment Outcome MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Acetylglucosamine MeSH
• Adjuvants, Immunologic MeSH
• Glycoconjugates MeSH
• Hemocyanins MeSH
• keyhole-limpet hemocyanin MeSH Browser
• Antineoplastic Agents MeSH