Collagen-induced arthritis: severity and immune response attenuation using multivalent N-acetyl glucosamine

Abstract

SummaryRheumatoid 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.

Increased chemotaxis and activity of circulatory myeloid progenitor cells may contribute to enhanced osteoclastogenesis and bone loss in the C57BL/6 mouse model of collagen-induced arthritis

“…In contrast to profound pannus invasion of the articular cartilage seen in DBA/1 strain , joint pathology in B6 mice is characterized by pronounced osteitis within the subchondral compartment, coinciding with the areas of TRAP + osteoclasts adjacent to the subchondral bone surfaces. As well as local changes, systemic bone loss of axial and appendicular skeleton was observed in different rodent models of arthritis . In our model, in vivo bone formation was suppressed and bone resorption was enhanced resulting in decreased trabecular bone volume.…”

Resistance of novel mouse strains different in MHC class I and the NKC domain to the development of experimental tumors

“…Cytotoxicity assay. The cytotoxic activity was estimated using the standard 51 Cr-release assay (30). Mouse spleen cells (effectors) were seeded in pentaplicates into roundbottomed 96-well microtiter plates (Nunc).…”

Dietary Natural N-Acetyl-d-Glucosamine Prevents Bone Loss in Ovariectomized Rat Model of Postmenopausal Osteoporosis

“…NAG has been reported to facilitate hyaluronic acid synthesis and improve wound healing. Furthermore, NAG possess anti-oxidant and immune-modulating effects and can regulate liver function and treat immuno-hepatic injury in clinical settings [ 16 , 17 ]. There has been an increasing demand for NAG being used in natural food additives.…”