M Feldmann

..We assessed the anti-inflammatory effects of a novel PDE4 inhibitor, apremilast, in human synovial cells from rheumatoid arthritis (RA) patients, as well as two murine models of arthritis...

..Disabling the interleukin (IL)-1 signaling pathway is sufficient to reduce inflammation and ameliorate the disability...

..The objective of the present study was to identify alternative splice variants (ASV) from cell surface receptor genes, and to determine whether the novel proteins encoded exert therapeutic activity in an in vivo model of arthritis...

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..This review summarizes the findings of a 1-day meeting devoted to the subject with the aim of coordinating efforts...

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..Their role as potential therapeutic targets is also highlighted...

..There are still many limitations, but the prospects for the future are intriguing...

..The work with TNF clearly demonstrated the importance of cytokines in medicine as well as the capacity of mAbs (or receptor fusion proteins) to be used long-term in large populations, thus changing the therapeutic landscape...

..This success has encouraged a burgeoning industry of biologicals for chronic diseases...

..The development of anti-TNF therapy is a key step forward in rheumatology as it is the first new therapy for based on investigating the molecular mechanisms of this disease. This chapter reviews how this discovery was made...

..My current scientific challenge is exploring the hypothesis of whether all major medical needs can be approached via cytokine blockade...

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..Focus will be on the TNF-dependent cytokine cascade and what it means, and potential new approaches to treatment. Finally, an entertaining challenge: might many or even all unmet clinical needs be dealt with through cytokine analysis?..

..Studying the intracellular signalling mechanism used by dendritic cells would provide an insight into the functioning of these cells and give clues to strategies for immunomodulation...

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..Combined anti-TNF-alpha/anti-CD4 treatment almost completely blocked the expression of IL-1beta, thereby confirming the ability of this form of combination therapy to prevent IL-1ss-mediated pathology...

..These data also highlight the potential problems in extrapolating the function of signaling pathways between primary and transfected cell lines...

..To evaluate the clinical efficacy of a novel synthetic peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonist, CLX-090717, in several in vitro cell culture systems and murine CIA, an experimental model of RA...

..These data indicate that CD40 ligation regulates cell contact mediated macrophage IL-10 and that the route of differentiation determines the cytokine profile...

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..CONCLUSION: Chronic relapsing homologous collagen-induced arthritis is a valuable model for identifying remission-inducing antiarthritic drugs and has predictive value with respect to their joint-protective potency...

..These findings provide further insights into the diverse interplay of immune processes involved in autoimmune inflammation and the mechanism of cytokine immunotherapy...

..The results of this study have implications for the future investigation of molecular pathways in inflammatory lung disease...

..The future developments of anti-TNFalpha and anti-cytokine therapy in general will be interesting...

..Infliximab (a mAB), and etanercept (a sTNF-R-Fc fusion protein) have been approved by regulatory authorities in the United States and Europe for treating RA, and they represent a significant new addition to available therapeutic options...

..New approaches to studying TNF regulation in RA and of elucidating the controversial role of T cells in this complex disease will be described...

..This finding has potential implications for the development of therapeutic agents for use in various pathological conditions of the immune system, including allergy and autoimmunity, and also in transplantation...

..This study describes MyD88lpr as a potential adjuvant for vaccinations, which would be able to target DC specifically...

..Thus the action of IL-10 may differ depending on the local cytokine microenvironment produced by the gene-secreting cell types...

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..These findings define NIK, and possibly other inducers of NF-kappaB activation, as a potent adjuvant strategy that offers great potential for genetic vaccine development...

..The era of anti-cytokine therapeutics is just dawning...

..These results show that FAA alone can induce cytokine release from primed target cells. This may be associated with the therapeutic effect and/or toxicity of the agent...

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..Mammalian cells transfected with the entire TNF receptor cDNA bind radiolabeled TNF alpha with an affinity of 2.5 x 10(-9) M. This binding can be competitively inhibited with unlabeled TNF alpha or lymphotoxin (TNF beta)...

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..We therefore investigated whether infliximab, a chimeric human-mouse anti-TNFalpha monoclonal antibody would provide additional clinical benefit to patients who had active rheumatoid arthritis despite receiving methotrexate...

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..The effective downregulation of antigen-specific T-cell responses following blockade of NF-kappaB in DCs could be a useful approach for immunomodulating inflammatory T-cell responses...

..The targeting of PRR intracellular signalling networks would allow for greater specificity and reduced systemic toxicity. The present review examines the successes seen with overexpression or repression of PRR signalling molecules...

..The actions of AdvsFlt-1 are likely to be mediated by reduced synovial neovascularization, and these results support the concept that VEGF blockade may be an effective therapeutic adjunct for the treatment of RA...

..Whether targeting TLRs and their downstream signaling pathway will prove to be a successful approach for the treatment of these devastating diseases remains to be determined...

..To investigate the mechanism that leads to the spontaneous production of tumor necrosis factor alpha (TNFalpha) in rheumatoid arthritis (RA) synovial tissue...

..This discovery heralded a new era of targeted and highly effective therapeutics for rheumatoid arthritis and, subsequently, other chronic inflammatory diseases...

..NF-kappaB regulates many of the genes involved in immune and inflammatory responses, and our study adds the angiogenic cytokine VEGF to the list of NF-kappaB-dependent cytokines...

..The study was undertaken to establish whether IL-10 can ameliorate arthritis in the collagen-induced arthritis (CIA) model of RA...

..The data confirm that IL-15 plays a role in RA and suggests that IL-21 is also involved in driving the pro-inflammatory cytokine response in RA...

..Thus, TLRs not only protect against infection but may also promote the inflammatory and destructive process in RA...

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..These results indicate despite disappointing results with p38 MAPK inhibitors in the clinic, this kinase is a valid target in rheumatoid disease...

..However, since the antibodies were only able to cross-react with partly denatured TNFalpha, evaluation of safety and tumour responses to the TNFalpha vaccine was compromised...

..The mechanism of action involves reduced cellularity of synovium as anticipated, along with a reduction in TNF production from inflammatory cells in the synovium. The latter mechanism needs further mechanistic analysis...

..This study suggests that TNF autovaccination is a cheaper and highly efficient alternative that can block TNF and reduce metastasis in vivo and trials with TNF autovaccination are already underway in patients with metastatic cancer...

..To evaluate the safety and efficacy of a chimeric monoclonal antibody to tumor necrosis factor alpha (TNF alpha) in the treatment of patients with rheumatoid arthritis (RA)...

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..This would suggest that TNF-induced activation of Rac, lies upstream of NF-kappaB activation, and that the inhibition of this pathway results in inhibition of cytokine production...

..Targeting intracellular signaling pathways may allow for greater specificity of the adjuvant, as well as reducing systemic toxicity. Studies targeting these pathways are discussed, as well as their potential applications in the future...

..This study highlights that different molecular mechanisms of NFkappaB activation may be involved downstream of stimuli which activate the endothelial lining of blood vessels...

..Cytokines driving angiogenesis are also important in disease chronicity and thus might be valid therapeutic targets...

..However, up to 40% of individuals with radiologic damage are asymptomatic. The purpose of this study was to assess the role of the endogenous opioid system in delaying the onset of pain in a murine model of osteoarthritis (OA)...

..To evaluate the therapeutic potential of the human epidermal growth factor receptor (HER) family inhibitor, herstatin, in an animal model of arthritis...

..We then validated the model using anti-tumor necrosis factor (anti-TNF) therapy, which has analgesic effects in models of inflammation as well as in human RA...

..This review describes therapies that are approved, in clinical trials or under pre-clinical investigation at the laboratory level, particularly focusing on cytokines, although other therapeutic targets of interest are mentioned...

..There is now extensive clinical use of anti-TNFalpha biologicals for severe rheumatoid arthritis in the US and Europe...

..Thus, by reducing the level of PGE(2), NSAIDs can increase TNF production and may exacerbate the proinflammatory environment both within the rheumatoid arthritis joint and the systemic environment...

..They also suggest that, unlike post-operative pain, induction of pain in OA may not necessarily be driven by classical inflammatory processes...

..We explored the effects of blocking TLR-2, TLR-4, and myeloid differentiation primary response gene 88 (MyD88), a signaling adaptor shared by most TLRs and interleukin-1 receptor (IL-1R), in an in vitro model of human atherosclerosis...

..In conclusion, VIP may represent an efficaceous anti-arthritic treatment modulating macrophage and T-cell cytokine profiles when used alongside a phosphodiesterase inhibitor...

..The profound suppressive effects on cellular immune responses and on the production of proinflammatory mediators all indicate its usefulness as a novel nonpsychoactive, synthetic antiinflammatory product...

..This cascade of events is discussed in the context of disease initiation/progression, with particular reference to atherosclerosis and rheumatoid arthritis, and to potential novel therapeutic targets for their treatment...

..Furthermore, new approaches to blockade of signaling mediated by bioactive TNF might have the potential to generate higher-magnitude clinical responses than are currently elicited...

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..Better understanding of these pathogenic pathways will inform the development of new therapeutic approaches leading to more complete and sustained disease remissions...

..It is our belief that the future of immunotherapy in the clinic will depend to some extent upon the availability of biomarkers for defining biological signatures of immune function in vivo...

..In the clinic, monoclonal antibodies are proving to be safe and effective for the treatment of a wide range of diseases including rheumatoid arthritis, Crohn's disease, spondyloarthropathies, psoriasis and allograft rejection...

..Recent contributions to this field, derived from in vivo studies in animal models of autoimmunity, and increasingly from clinical trials, have greatly enhanced our understanding of this field...

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..These observations suggest that CD40 ligation induces macrophage IL-10 and TNF-alpha production, the mechanism of which is p70S6K-dependent yet bifurcates at the level of PI3K and p42/44 MAPK...

..In conclusion, we demonstrated that RelB/p50 was active only in DC expressing both RelB and p50, and induced CCL19 production, but not DC maturation...

..IL-23 is a pro-inflammatory cytokine proposed to be central to the development of autoimmune disease. We investigated whether IL-23, together with the downstream mediator IL-17A, was present and functional in RA in humans...

..We explored whether systemic inflammation, in response to surgical trauma, triggers hippocampal inflammation and subsequent memory impairment, in a mouse model of orthopedic surgery...

..Therefore, the purpose of this study was to investigate the involvement of SIGIRR in regulating inflammation in disease-relevant models...

..In the present work it is demonstrated that partial myeloablation induces a relative expansion of T(regs) that is sufficient to mediate immunological tolerance...

..Together, these data suggest that TLR8 may play a role in driving TNF production in RA. Because this receptor can be inhibited by small m.w. molecules, it may prove to be an important therapeutic target...

..This is the first report of such cell type- and species-specific response for any TLR stimulation and helps to explain important difficulties in correlating murine models of inflammatory diseases and human inflammation...

..These data suggest that antiangiogenic therapies, which block formation of new blood vessels and hence reduce synovial expansion, might be effective in treating rheumatoid arthritis...

..In addition, our results support IKK2 as a potential therapeutic target for the down-regulation of unwanted immune responses that may occur during transplantation or autoimmunity...

..We conclude that TRAM is an adaptor protein for both TLR4 and TLR2/6 signaling in SFs, HUVECs, and murine embryonic fibroblasts, but cannot demonstrate a role in human macrophages...

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..IL-10 production in RA-SMCs and M-CSF-primed macrophages, activated by interaction with Tck, is PI3K- and p70S6K-dependent...

..In this brief review we discuss the effects of NF-kappaB blockade in rheumatoid arthritis, inflammation and immunity, and consider possible therapeutic targets within the NF-kappaB family...