TNF-a pivotal role in rheumatoid arthritis? Br J Rheumatol. as CNI-1493 with a defined mode of action provides a useful tool for dissecting and understanding important pathogenic mechanisms operating in the development of chronic arthritis. Keywords: collagen-induced arthritis, immunotherapy, tetravalent guanylhydrazone, immunopharmacology, tumour necrosis factor-alpha INTRODUCTION CIA in susceptible rat strains constitutes a model of autoimmunity that shares a number of pathological, immunological, and genetic features with rheumatoid arthritis (RA) [1C5]. The dark Agouti (DA) rat is particularly susceptible and offers a stable, reproducible model with an erosive, chronic polyarthritis developing in 100% of immunized animals when CIA is usually induced with Cisplatin homologous collagen type II (CII) in the presence of Freund’s incomplete adjuvant (FIA) [4,5]. Numerous studies with existing disease-modifying drugs have established CIA as a relevant model for identification of successful therapeutic approaches in arthritis [6C8]. Monokines, such as IL-1 and TNF-, have been demonstrated to be particularly important mediators of local inflammatory responses in arthritis [9,10]. These cytokines are present in abundance in synovial fluid and synovial tissue in joints of patients with RA [11,12] as well as in corresponding tissues in mice with CIA [13,14]. TNF- has been detected in the synovial membrane and especially at the cartilageCpannus junction of patients with RA [15]. Furthermore, TNF- has been demonstrated to induce cartilage and bone resorption in joints [16,17]. Another piece of evidence for a principal role for TNF- in the pathogenesis of arthritis is the finding that transgenic mice with constitutive excessive production of TNF- spontaneously develop chronic polyarthritis, which is usually prevented by administration of TNF- antibodies [18]. Specific therapy targeted against TNF- alone using anti-TNF- MoAbs or soluble TNF- receptors has been effective in murine CIA by reducing the incidence and severity of disease [19C22]. Neutralizing TNF- MoAb therapy in patients with severe RA has also been successful [23,24]. Thus, TNF- represents an important therapeutic target in inflammatory joint diseases. Recently, a tetravalent guanylhydrazone (CNI-1493) was developed as an inhibitor of macrophage activation [25C27]. One major effect exerted by CNI-1493 on activated macrophages was decided to be suppression of TNF- synthesis, mediated by a dose-dependent inhibition of the translation of TNF mRNA via an conversation with the p38 MAP kinase [28,29]. CNI-1493, as opposed to effects mediated by glucocorticoids, even retained its TNF-suppressive effects on interferon-gamma (IFN-)-primed macrophages [26]. The aim of the present study was to investigate the potential of this new compound to counteract inflammatory joint disease. Clinical effects after prophylactic and therapeutic intervention with CNI-1493 in CIA in the DA rat strain have been studied as well as immunohistological examinations Rabbit Polyclonal to HNRNPUL2 of the joint tissue. MATERIALS AND METHODS Animals Male DA rats, 2C3 months aged with a mean weight of 220C230 g, were used Cisplatin in our study. The animals were originally purchased from the Central Institute for Laboratory Animal Breeding (Hanover, Germany), and were then kept and bred at the animal unit at the Karolinska Hospital in Stockholm, Sweden. Rats were maintained under climate-controlled conditions with a 12-h light/dark cycle. The health status of the animal colony was monitored according to the guidelines from the Swedish Veterinary Board (SVA) and reported free from screened pathogens. The rats were fed standard rodent chow and water values are based on overall comparisons between the means of all time points compared for each group. Unpaired = 8 in each group in the first trial and = 7 in each group in the second trial). All Cisplatin treatment groups differed significantly when compared with placebo. values compare group.
