Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: HUMANGGP:017444 (TNF)
 61,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Crohn's Disease (CD) is a chronic inflammatory bowel disease (IBD) that can affect any portion of the gastrointestinal tract and can cause significant morbidity. A variety of animal models of both acute and chronic intestinal inflammation have been developed to investigate disease pathogenesis and novel treatment modalities. These include chemically induced, genetically manipulated and immune-mediated models of gut inflammation, each of which possesses similarities to human IBD and offers unique advantages for studying specific aspects of disease pathogenesis. However, the majority of these models are characterized by colitis and, unlike human CD, do not involve the small intestine. More recently, murine models of chronic ileal inflammation have been characterized that spontaneously develop and closely resemble human CD with regard to disease location, histologic features and clinical response to therapy. Two mouse models of experimental ileitis will be discussed in this review: the TNF DeltaARE and SAMP1/YitFc strains. Studies using these new models might provide important insight into the pathogenesis of human CD and test the efficacy of potential therapies to treat this devastating disease.
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PMID:Mouse models for the study of Crohn's disease. 1276 27

Substantial evidence suggests a central role for TNF-alpha in the pathogenesis of IBD. This molecular observation has been supported by clinical trials with anti-TNF therapies. The most extensively investigated among the various anti-TNF agents is infliximab. Clinical trials to date have demonstrated its efficacy in inducing remission in patients with moderately active, refractory Crohn's disease (CD) and in managing patients with CD complicated by fistulas. One advantage of infliximab is its rapid onset of action. However, as expected with most medications used to treat patients with IBD, the effect of infliximab is of limited duration, with the response lasting 2-3 months in most patients. The efficacy of repeated infusions of infliximab in maintaining remission in patients with inflammatory CD has been demonstrated in one trial to date. The results from the ACCENT I trial should soon be available. Many other important questions regarding the use of infliximab remain unanswered. These include the optimal schedules of infusions, the effect of concomitant therapy with aminosalicylates, immunomodulators and antibiotics, and the timing and indication of using infliximab in the general management algorithm of a patient with CD. Certainly, the efficacy of infliximab in the treatment of ulcerative colitis (UC) remains to be further explored in a controlled fashion, though preliminary uncontrolled data suggests efficacy. As experience with infliximab use accumulates, more data will become available regarding its safety with either short-term or long-term use. A large body of evidence exists regarding the short-term safety of infliximab. The concern of increased risk of hypersensitivity-like reactions with longer interval between treatments will also need to be addressed. The currently available data supports that infliximab is safe and well tolerated. Other anti-TNF therapies will also need to be investigated with the same rigor before widespread use can be advocated. In addition to these agents, advances in molecular engineering techniques have further expanded the array of biologic therapies available to treat IBD. These newer therapies hold promise in targeting specific pathways of the pathogenesis of IBD that may be different from all prior therapies. Certainly, the anti-TNF therapies and others aforementioned have taken the field of IBD into a new and exciting generation, the biological era. (c) 2001 Prous Science. All rights reserved.
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PMID:The role of biological therapy in inflammatory bowel disease. 1278 3

The first-line therapy for inflammatory bowel disease flares is typically medical in nature. Glucocorticoids are a mainstay for the treatment of severe inflammatory bowel disease. Aminosalicylates are efficacious in the treatment of active mild- to- moderate disease. Infliximab, a chimeric monoclonal anti-TNF alpha antibody can be used in refractory Crohn's disease. The recurrence rate after surgery or medical therapy is high. Therefore the introduction of a maintenance therapy is important in patients with repetitive flares. In patients with ulcerative colitis aminosalicylates are useful as maintenance therapy. In severe ulcerative colitis or in Crohn's disease immune suppressive strategies such as a therapy with azathioprine, 6-mercaptopurine or methotrexate should be considered. In Crohn's patients with fistula surgical treatment or a therapy with antibiotics, immunosuppressants or infliximab is recommended.
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PMID:[Does conservative therapy of chronic inflammatory bowel diseases still play a role?]. 1281 33

Advances in understanding pathogenesis and developing new therapies are hastened by the use of effective animal models of disease. In inflammatory bowel disease, such as Crohn's disease, a variety of models have been used, including the IL-10 knockout mouse. However, in order to be truly valuable, the models need to respond to existing therapy in a way which resembles the human disease. In the light of recent developments, in which refractory Crohn's disease responds well to anti-TNF antibody therapy, we set out to validate the IL-10 knockout model of Crohn's disease by examining its response to anti-TNF therapy. We developed a new scoring system for IL-10 knockout mice, similar to the Crohn's Disease Activity Index in humans, analysed stool samples for cytokines and compared the findings with histology. We found that anti-TNF antibody therapy starting at 4 weeks markedly ameliorated the disease, as judged by the clinical score or by histological analysis of the gut. Furthermore, analysis of stool samples for cytokines revealed a marked diminution of inflammatory cytokines, adding a further accurate measure of the improvement. This model may thus be useful for evaluating other therapeutic modalities of relevance to Crohn's disease.
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PMID:Validation of the interleukin-10 knockout mouse model of colitis: antitumour necrosis factor-antibodies suppress the progression of colitis. 1282 76

The development of tumor necrosis factor-alpha (TNF alpha) inhibitors has been one of the most active areas of drug development over the last ten years for the treatment of inflammatory diseases. Following the definition of TNF alpha as a key mediator of inflammatory disease and the success demonstrated by various anti-TNF alpha strategies in the treatment of rheumatoid arthritis and inflammatory bowel disease, many investigators have sought to refine mechanisms by which to modulate TNF alpha in vivo. Many advances are presently being made in the understanding of how TNF alpha production is regulated, and with this knowledge comes the identification of new targets and pathways for therapeutic intervention. Here, we review the development of the currently available therapeutics and the progressive steps that are being made to improve clinical efficacy of anti-TNF alpha strategies.
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PMID:Mechanisms for modulating TNF alpha in immune and inflammatory disease. 1282 58

Bristol-Myers Squibb Pharma Co is developing the tumor necrosis factor-alpha (TNF alpha) converting enzyme inhibitor BMS-561392 (DPC-333) for the potential treatment of diseases characterized by overproduction of TNF alpha, such as rheumatoid arthritis (RA). A phase IIa trial in RA patients had commenced by April 2001, and by October 2002, BMS-561392 was also under investigation for the potential treatment of inflammatory bowel disease.
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PMID:BMS-561392. Bristol-Myers Squibb. 1283 56

Tumour necrosis factor alpha (TNFalpha), named for its antitumour properties, was isolated almost 30 years ago. It is a vital member of the multifunctional TNF superfamily and has important roles in immunity and cellular remodelling as well as influencing apoptosis and cell survival. Its central role in inflammation has led to the development of TNFalpha antagonists as effective therapies for rheumatoid arthritis and inflammatory bowel disease. In this review, we discuss the evidence which has accumulated during the past decade that implicates TNFalpha in inflammatory pathways that increase tumorigenesis. There is convincing evidence that under specific conditions TNFalpha is a tumour promoter and helps to produce the toxic effects associated with conventional cancer therapy, such as the cytokine release syndrome and cisplatin-induced nephrotoxicity. Several trials have been set up to investigate the role of TNFalpha antagonists in cancer. It is hoped that these agents inhibit the neoplastic process either alone or in combination with other agents, and ameliorate the side effects of cancer therapy.
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PMID:Tumour necrosis factor alpha: a potential target for the therapy of solid tumours. 1296 78

TL1A is a novel TNF-like factor that acts as a costimulator of IFN-gamma secretion through binding to the death domain-containing receptor, DR3. The aim of this study was to test the hypothesis that TL1A may play an important role in inflammatory bowel disease (IBD) by functioning as a Th1-polarizing cytokine. The expression, cellular localization, and functional activity of TL1A and DR3 were studied in intestinal tissue specimens as well as isolated lamina propria mononuclear cells from IBD patients and controls. TL1A mRNA and protein expression was up-regulated in IBD, particularly in involved areas of Crohn's disease (CD; p < 0.03 vs control). TL1A production was localized to the intestinal lamina propria in macrophages and CD4(+) and CD8(+) lymphocytes from CD patients as well as in plasma cells from ulcerative colitis patients. The amount of TL1A protein and the number of TL1A-positive cells correlated with the severity of inflammation, most significantly in CD. Increased numbers of immunoreactive DR3-positive T lymphocytes were detected in the intestinal lamina propria from IBD patients. Addition of recombinant human TL1A to cultures of PHA-stimulated lamina propria mononuclear from CD patients significantly augmented IFN-gamma production by 4-fold, whereas a minimal effect was observed in control patients. Our study provides evidence for the first time that the novel cytokine TL1A may play an important role in a Th1-mediated disease such as CD.
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PMID:Expression, localization, and functional activity of TL1A, a novel Th1-polarizing cytokine in inflammatory bowel disease. 1456 67

Currently used standard treatment in IBD is effective and sufficient for the majority of patients. Published numbers regarding therapy refractoriness are probably related to referral centers and not representative. Pharmacological optimization of available drugs improves the standard situation further. Biological therapies in a larger meaning are studied intensively, but obviously hopes are to some extent not real. Biological and for some principles clinical effects (i.e. TNF antibodies, CD4 antibodies) are proven, the effects are, however, limited and long-term risks and results are not clarified. Numerous approaches are not clinically relevantly effective which is, in particular, true for those inhibiting single mediators. A number of alternative concepts such as hormones and growth factors could be effective and will be studied further. In particular probiotics may be a development of the future and they belong to the 'biologic treatments' in the true sense.
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PMID:Biological therapy in IBD. Anti-tumor necrosis factor-alpha and others. 1457 Nov 15

Immunologically mediated tissue damage in the gut is associated with increased production of proinflammatory cytokines, which activate the transcription factor NF-kappaB in a variety of different cell types. The mechanisms/factors that negatively regulate NF-kappaB in the human gut and the pathways leading to the sustained NF-kappaB activation in gut inflammation remain to be identified. Pretreatment of normal human intestinal lamina propria mononuclear cells (LPMC) with transforming growth factor-beta1 (TGF-beta1) resulted in a marked suppression of TNF-alpha-induced NF-kappaB p65 accumulation in the nucleus, NF-kappaB binding DNA activity, and NF-kappaB-dependent gene activation. TGF-beta1 also increased IkappaBalpha transcripts and protein in normal LPMC. In marked contrast, treatment of LPMC from patients with inflammatory bowel disease with TGF-beta1 did not reduce TNF-induced NF-kappaB activation due to the overexpression of Smad7. Indeed inhibiting Smad7 by specific antisense oligonucleotides increased IkappaBalpha expression and reduced NF-kappaB p65 accumulation in the nucleus. This effect was due to endogenous TGF-beta1. TGF-beta1 directly stimulated IkappaBalpha promoter transcriptional activity in gut fibroblasts in vitro, and overexpression of Smad7 blocked this effect. These data show that TGF-beta1 is a negative regulator of NF-kappaB activation in the gut and that Smad7 maintains high NF-kappaB activity in gut inflammation by blocking TGF-beta1 signaling.
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PMID:A failure of transforming growth factor-beta1 negative regulation maintains sustained NF-kappaB activation in gut inflammation. 1460 Jan 58


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