Tumour necrosis factor α as a therapeutic target for immune-mediated inflammatory diseases

The Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College London, 1 Aspenlea Road, London W68LH, UK.
Current Opinion in Biotechnology (Impact Factor: 7.12). 01/2005; 15(6):557-63. DOI: 10.1016/j.copbio.2004.09.005
Source: PubMed


Preclinical studies have identified and validated tumour necrosis factor alpha (TNFalpha) as a key disease molecule and therapeutic target for immunotherapeutic intervention in many immune-mediated inflammatory diseases. Clinical indications include rheumatoid arthritis, Crohn's disease, ankylosing spondylitis and psoriasis. Recent clinical findings indicate that many chronic inflammatory disorders share certain pathogenic pathways, whereas others are limited to particular disease phenotypes. Better understanding of these pathogenic pathways will inform the development of new therapeutic approaches leading to more complete and sustained disease remissions.

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    • "L'ultimo esempio è costituito dal nebivololo, solamente da poco tempo approvato nel trattamento dell'insufficienza cardiaca [6]. Alcuni esempi di utilizzo off-label in medicina interna sono riportati nelle Tabb. 1 e 2 [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19]. "

    05/2013; 1(3):69. DOI:10.4081/itjm.2007.3.69
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    • "As DC migration is essential during both steady-state conditions in the absence of inflammation, as well as during inflammation, DCs were co-cultured either with resting fibroblasts or with fibroblasts stimulated with TNFa and IL-1b to mimic a proinflammatory tissue microenvironment. TNFa and IL-1b were chosen as stimuli, as they are highly expressed during cutaneous inflammation (Taylor et al., 2004; Aggarwal et al., 2006). Resting fibroblasts did not significantly enhance the secretion of MMP-9 from immature DCs. "
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    ABSTRACT: Migration of dendritic cells (DCs) from skin to lymph nodes on activation is an essential step in the initiation of an adequate immune response. The dermal microenvironment including stromal cells and their soluble factors might be involved in the regulation of DC migration. To focus on the role of dermal fibroblasts, we studied whether interaction of DCs with fibroblasts promotes the migration of DCs. DCs were co-cultured with resting fibroblasts or with tumor necrosis factor (TNF)alpha/IL-1beta-activated fibroblasts to mimic an inflammatory microenvironment. Interaction of DCs with TNFalpha/IL-1beta-stimulated fibroblasts increased the secretion of matrix metalloproteinase-9 (MMP-9) from DCs within 6 hours compared with DCs alone or DCs stimulated with lipopolysaccharide or TNFalpha/IL-1beta. In contrast, unstimulated fibroblasts did not affect MMP-9 secretion. IL-6 released by TNFalpha/IL-1beta-stimulated fibroblasts was identified as a factor responsible for fibroblast-stimulated MMP-9 secretion from DCs. In accordance with the elevated MMP-9 release, on co-culture with TNFalpha/IL-1beta-stimulated fibroblasts, DCs migrated significantly more effectively through matrigel matrices than did TNFalpha/IL-1beta-stimulated DCs. This was inhibited by a selective blocking of MMP-9, indicating the importance of MMP-9 for this migratory capacity of DCs. In summary, fibroblasts in the local dermal microenvironment are capable of potentiating the migratory capacity of DCs, and thus have the potential to actively participate in the regulation of a cutaneous immune response.
    Journal of Investigative Dermatology 09/2009; 130(2):444-54. DOI:10.1038/jid.2009.253 · 7.22 Impact Factor
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    • "The inhibitory profiles obtained for such gene surrogates were usually found to be similar to those observed in the corresponding endogenous genes assayed at the mRNA level (54). For our studies, we used murine TNF-α as a model target RNA, as the human form of this cytokine has been validated as a therapeutic target for treatment of chronic inflammation associated with many diseases, including rheumatoid arthritis, psoriasis and HCV-related liver necrosis (55). Since the target in the TNF22-Luc reporter is upstream of the AUG start codon, we speculate that the mechanism of translation inhibition is steric interference with the formation of the initiation complex or ribosome scanning. "
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    ABSTRACT: We have developed a novel class of antisense agents, RNA Lassos, which are capable of binding to and circularizing around complementary target RNAs. The RNA Lasso consists of a fixed sequence derived from the hairpin ribozyme and an antisense segment whose size and sequence can be varied to base pair with accessible sites in the target RNA. The ribozyme catalyzes self-processing of the 5'- and 3'-ends of a transcribed Lasso precursor and ligates the processed ends to produce a circular RNA. The circular and linear forms of the self-processed Lasso coexist in an equilibrium that is dependent on both the Lasso sequence and the solution conditions. Lassos form strong, noncovalent complexes with linear target RNAs and form true topological linkages with circular targets. Lasso complexes with linear RNA targets were detected by denaturing gel electrophoresis and were found to be more stable than ordinary RNA duplexes. We show that expression of a fusion mRNA consisting of a sequence from the murine tumor necrosis factor-alpha (TNF-alpha) gene linked to luciferase reporter can be specifically and efficiently blocked by an anti-TNF Lasso. We also show in cell culture experiments that Lassos directed against Fas pre-mRNA were able to induce a change in alternative splicing patterns.
    Nucleic Acids Research 11/2008; 36(21):6752-66. DOI:10.1093/nar/gkn637 · 9.11 Impact Factor
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