A pilot study of IL-1 inhibition by anakinra in acute gout

Monosodium urate crystals stimulate monocytes and macrophages to release IL-1β through the NALP3 component of the inflammasome. The effectiveness of IL-1 inhibition in hereditary autoinflammatory syndromes with mutations in the NALP3 protein suggested that IL-1 inhibition might also be effective in relieving the inflammatory manifestations of acute gout. The effectiveness of IL-1 inhibition was first evaluated in a mouse model of monosodium urate crystal-induced inflammation. IL-1 inhibition prevented peritoneal neutrophil accumulation but TNF blockade had no effect. Based on these findings, we performed a pilot, open-labeled study (trial registration number ISRCTN10862635) in 10 patients with gout who could not tolerate or had failed standard antiinflammatory therapies. All patients received 100 mg anakinra daily for 3 days. All 10 patients with acute gout responded rapidly to anakinra. No adverse effects were observed. IL-1 blockade appears to be an effective therapy for acute gouty arthritis. The clinical findings need to be confirmed in a controlled study

Pharmacological Inhibition of Nicotinamide Phosphoribosyltransferase/Visfatin Enzymatic Activity Identifies a New Inflammatory Pathway Linked to NAD

Nicotinamide phosphoribosyltransferase (NAMPT), also known as visfatin, is the rate-limiting enzyme in the salvage pathway of NAD biosynthesis from nicotinamide. Since its expression is upregulated during inflammation, NAMPT represents a novel clinical biomarker in acute lung injury, rheumatoid arthritis, and Crohn's disease. However, its role in disease progression remains unknown. We report here that NAMPT is a key player in inflammatory arthritis. Increased expression of NAMPT was confirmed in mice with collagen-induced arthritis, both in serum and in the arthritic paw. Importantly, a specific competitive inhibitor of NAMPT effectively reduced arthritis severity with comparable activity to etanercept, and decreased pro-inflammatory cytokine secretion in affected joints. Moreover, NAMPT inhibition reduced intracellular NAD concentration in inflammatory cells and circulating TNFα levels during endotoxemia in mice. In vitro pharmacological inhibition of NAMPT reduced the intracellular concentration of NAD and pro-inflammatory cytokine secretion by inflammatory cells. Thus, NAMPT links NAD metabolism to inflammatory cytokine secretion by leukocytes, and its inhibition might therefore have therapeutic efficacy in immune-mediated inflammatory disorders

Maturation et apoptose des cellules dendritiques in vivo

Doctorat en Sciencesinfo:eu-repo/semantics/nonPublishe

NEW METHOD FOR THE TREATMENT OF INFLAMMATORY DISEASES

Publication info: WO2008026018 - 2008-03-06info:eu-repo/semantics/publishe

Fonction et maturation des cellules dendritiques in vivo

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Activation of murine T cells by bacterial superantigens requires B7-mediated costimulation.

Staphylococcus enterotoxins bind class II MHC molecules on antigen-presenting cells (APC) and stimulate T cells expressing appropriate V beta gene products. Although the role of non-TcR-associated costimulatory receptors during antigen-specific T cell stimulation has been clearly established, the involvement of costimulatory activity in T cell activation by superantigens (SAgs) has been the matter of controversy. The aim of this study was to evaluate the role of the costimulatory-receptor ligand molecules CD28/B7 on bacterial SAg-mediated activation of naive murine T cells. We demonstrate in this report that a combination of monoclonal antibodies to murine B7.1 and B7.2 molecules inhibits the in vitro response of naive T cells to SAgs SEA, SEB, and TSST-1. The inhibition of T cell responses required simultaneous blocking of B7.1 and B7.2, suggesting that either B7.1 or B7.2 is sufficient to provide costimulatory signals to naive T cells in response to bacterial exotoxins. Inhibition of T cell activation by antibodies to B7-related molecules can be overcome by antibodies to CD28, a finding in agreement with the hypothesis that CD28-mediated signals participate in T cell activation by bacterial SAgs. These observations suggest that, as demonstrated for conventional antigen, T cell activation by SAgs requires the coordinated participation of TcR- and CD28-derived signals.In VitroJournal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Positive and negative regulation of dendritic cell function by lipopolysaccharide in vivo.

Journal Articleinfo:eu-repo/semantics/publishe