The complex pathogenesis of immune-mediated inflammatory diseases (IMIDs) has been extensively investigated and dysregulation of cytokines, such as tumour necrosis factor (TNF) has been shown to play a dominant role in the pathogenesis of various IMIDs, such as rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, psoriasis and psoriatic arthritis. The subsequent development of biological agents capable of blocking TNF has led to important advances in the pharmacotherapy of such diseases and confirmed the concept of a common pathophysiology among IMIDs with TNF having a predominant role. Five TNF inhibitors have currently been approved for treatment of one or more IMIDs; these include infliximab, etanercept, adalimumab, golimumab and certolizumab pegol. Given the similarities in the pathogenic background of IMIDs, one could expect that anti-TNF agents be similarly effective and with comparable tolerability profiles; however, this may not be the case. Structural and pharmacological differences among the anti-TNF drugs are likely to result in differences in efficacy and tolerability among the agents in the different IMIDs, together with differences in potency, therapeutic dose ranges, dosing regimens, administration routes, and propensity for immunogenicity. Among the five TNF inhibitors approved for treatment of IMIDs, adalimumab has the widest range of indications. Data from controlled clinical trials of adalimumab, showing its excellent efficacy and tolerability in a wide range of indications, are supported by real-world long-term data from observational studies, which confirm the value of adalimumab as a suitable choice in the management of IMIDs.
"JNK1 controls IL-1b production by mast cells in inflammatory arthritis (Guma et al., 2010), and IL-1b plays important roles in inflammation and destruction in synovial tissue, cartilage, bone, and joints in patients with RA (Tak and Bresnihan, 2000). TNF, mainly produced by macrophages, can amplify the inflammatory cascade in RA, and five TNF inhibitors are currently approved for treatment of immunemediated inflammatory diseases, including RA (Armuzzi et al., 2014). Both IL-1b and TNF induce synoviolin, an E3 ubiquitin ligase expressed in synovial fibroblasts, which is involved in the overgrowth of synovial cells during RA (Gao et al., 2006). "
[Show abstract][Hide abstract] ABSTRACT: c-Jun N-terminal kinases (JNKs) participate in many physiological and pathological processes, including inflammatory diseases. Recently, we synthesized the sodium salt of 11H[1,2-b]quinoxalin-11-one oxime ( IQ-1S: ) and demonstrated that it is a high-affinity JNK inhibitor and inhibited murine delayed-type hypersensitivity. Here we show that IQ-1S: is highly specific for JNK and that its neutral form is the most abundant species at physiological pH. Molecular docking of the IQ-1S: syn isomer into the JNK1 binding site gave the best pose, which corresponded to the position of co-crystallized JNK inhibitor SP600125. Evaluation of the therapeutic potential of IQ-1S: showed that it inhibited matrix metalloproteinase 1 and 3 gene expression induced by interleukin (IL)-1β in human fibroblast-like synoviocytes and significantly attenuated development of murine collagen-induced arthritis (CIA). Treatment with IQ-1S: either prior to or after induction of CIA resulted in decreased clinical scores, and joint sections from IQ-1S: -treated CIA mice exhibited only mild signs of inflammation and minimal cartilage loss compared to those from control mice. Collagen II-specific antibody responses were also reduced by IQ-1S: treatment. In contrast, the inactive ketone derivative 11H-indeno[1,2-b]quinoxalin-11-one ( IQ-18: ) had no effect on CIA clinical scores or collagen II-specific antibody titers. IQ-1S: treatment also suppressed proinflammatory cytokine and chemokine levels in joints and lymph node cells. Finally, treatment with IQ-1S: increased the number of Foxp3(+)CD4(+)CD25(+) regulatory T cells in lymph nodes. Thus, the IQ-1S: can reduce inflammation and cartilage loss associated with CIA and can serve as a small-molecule modulator for mechanistic studies of JNK function in rheumatoid arthritis.
The American Society for Pharmacology and Experimental Therapeutics.
Journal of Pharmacology and Experimental Therapeutics 03/2015; 353(3). DOI:10.1124/jpet.114.220251 · 3.97 Impact Factor
"Schett, 2007), psoriasis (Tamilselvi et al., 2013), and type 2 diabetes (Crook, 2004), are due to an excessive immune response with large numbers of infiltrating immune cells and abnormally high production of proinflammatory cytokines, such as IL-1β and tumor necrosis factor-α. Many of the treatment options for these diseases focus on reducing or inhibiting immune mediators, such as tumor necrosis factor-α (Armuzzi et al., 2014), the JAK (Janus tyrosine kinase) pathway (Hsu and Armstrong, 2014), and IL-1β (Dinarello, 2011). Use of anti-inflammatories as a treatment option in bovine mastitis requires further investigation to determine what magnitude of immune response is effective for clearing a mammary infection while minimizing the damage to the host, as well as the effect of variable immune responses in the success or failure of mastitis treatments. "
[Show abstract][Hide abstract] ABSTRACT: Staphylococcus aureus is a common cause of chronic mammary gland infections in dairy cattle. However, the inflammatory response and duration of infection following pathogen exposure is variable between individual animals. To investigate interanimal differences in immune response, dermal fibroblast cultures were established from skin biopsies collected from 50 early lactation Holstein cows. The fibroblasts ability to produce IL-8 in response to a 24-h treatment with a synthetic toll-like receptor 2/6 agonist (Pam2CSK4) was used to assign a response phenotype to the animals. Five high-responding and 5 low-responding animals were then selected for an intramammary challenge with S. aureus to evaluate differences in the inflammatory response, chronicity of infection, and development of antibodies to the pathogen. All animals exhibited clinical symptoms of mastitis at 24 h postchallenge. Animals previously classified as high responders experienced a greater inflammatory response characterized by elevated levels of milk somatic cell count, IL-8, and BSA following the challenge compared with low responders. In addition, antibodies toward the challenge strain of S. aureus reached higher levels in whey from the challenged gland of high responders compared with low responders. Despite the antibody response, all 5 high responders were chronically infected for the 6-wk duration of the study, whereas 2 of the low responders cleared the infection, although 1 of these did become reinfected. The observed differences between animals classified as low and high responders based on their fibroblast responsiveness suggests that this cell type can be used to further examine the causes of interanimal variation in response to mammary infection.
Journal of Dairy Science 01/2015; DOI:10.3168/jds.2014-9075 · 2.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Progressive multifocal leukoencephalopathy (PML) is a rare, complex opportunistic infection of the central nervous system caused by the JC virus. This past decade, PML was increasingly recognized to be associated with the use of immunosuppressive and biologic agents. The risk for PML differs among these agents and remains difficult to quantify because of the complex pathogenesis of PML and the presence of confounding factors. This paper explores and updates the association of PML with different biologic and immunosuppressive agents and proposes an expanded classification system for the risk of PML. We identify three classes of drug that vary by PML risk, latency to infection, and underlying illness. We also review some of the most common agents with known associations to PML and explore risk mitigation strategies that aim to inform the decision-making process for clinicians and patients in the face of the changing incidence of PML and the growing landscape of immunologic agents.
Journal of NeuroVirology 11/2014; DOI:10.1007/s13365-014-0303-1 · 2.60 Impact Factor
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