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)

In addition to its well known proinflammatory effects, tumor necrosis factor-alpha (TNF-a) has complex effects on the growth, differentiation, and death of immune cells. TNF antagonists have had dramatic effects on the suppression of rheumatoid arthritis and other rheumatic inflammatory diseases. However, TNF inhibition of RA has led to an increased incidence of drug induced anti-dsDNA production, with cases of systemic lupus erythematosus as well as exacerbations of multiple sclerosis. While etanercept does not generally alter the course of Crohn's disease we describe a rare instance where this agent may have contributed to the development of clinically significant inflammatory bowel disease.
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PMID:Development of Crohn's disease in a patient taking etanercept. 1580 Oct 37

Infliximab, a chimeric antitumor necrosis factor alpha monoclonal antibody (anti-TNF alpha), has been recently shown to have a beneficial effect on pyoderma gangrenosum associated with inflammatory bowel disease. Patients with the syndromic triad of pyogenic sterile arthritis, pyoderma gangrenosum, and acne, an autoinflammatory process caused by mutations in the CD2 binding protein-1 (CD2BP1) gene, can have severe pyoderma gangrenosum. We describe a 14-year-old patient with this syndrome who was unresponsive to multiple therapies. A dramatic improvement in his pyoderma gangrenosum was observed after one infusion of infliximab, and a second infusion led to its resolution. Our observation extends the therapeutic use of infliximab to this component of PAPA syndrome.
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PMID:Dramatic improvement of pyoderma gangrenosum with infliximab in a patient with PAPA syndrome. 1591 80

LIGHT is a member of the TNF superfamily, which is transiently expressed on the surface of activated T lymphocytes and immature dendritic cells. Its known receptors are herpesvirus entry mediator (HVEM) prominently in T lymphocytes, and lymphtoxin beta receptor (LTbetaR) in stromal cells or nonlymphoid hematopoietic cells. Previous studies have shown that overexpression of LIGHT on T cells could lead to lymphocytes activation, inflammation, and tissue destruction focused on intestinal mucosal tissues. To address the role of LIGHT/HVEM signaling in colonic inflammation, an experimental colitis model induced by rectal administration of trinitrobenzene sulfonic acid (TNBS) was given a soluble LTbetaR-Ig fusion protein as a competitive inhibitor of LIGHT/HVEM pathway. Marked elevation of LIGHT expression was detected in colonic tissue of the experimental colitis. Treatment with LTbetaR-Ig significantly attenuated the progression and histological manifestations of the colonic inflammation and reduced the production of inflammatory cytokines including TNF-alpha, IL-1beta and IL-8. Moreover, LTbetaR-Ig treatment significantly down-regulated LIGHT expression, leading to reduced lymphocytes, particularly CD4+ T cells, infiltrating into the colonic inflammation tissue as shown by histological analysis. In addition, comparison of the therapeutic effects on TNBS-induced colitis between LTbetaR-Ig and mesalazine showed that both treatments were equally efficacious. We postulated that blockade of LIGHT/HVEM signaling by LTbetaR-Ig may ameliorate TNBS-induced colitis by down-regulating LIGHT expression, and therefore we envision that LTbetaR-Ig would prove to a promising strategy for the clinical treatment of inflammatory bowel disease.
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PMID:Lymphtoxin beta receptor-Ig ameliorates TNBS-induced colitis via blocking LIGHT/HVEM signaling. 1592 18

Tumour necrosis factor/cachecin (TNF-alpha) and lymphotoxin (LTalpha / TNF-alpha), 2 members of the TNF family of cytokines, have numerous biological functions, such as induction of apoptosis, cytotoxicity, inflammation, immunoregulation, proliferation and antiviral responses. Although TNF-alpha is produced by many cell types, the majority comes from activated macrophages. The related molecule, LT-alpha is produced mainly by activated lymphocytes and shares many of TNF's properties. TNF-alpha is active in both of its molecular forms, a secreted 17 kDa mature form and a transmembrane 26 kDa precursor. It induces activity by stimulating 2 distinct receptor subtypes, TNFR1 (55 kDa) and TNFR2 (75 kDa). The activation of TNFR1 is generally thought to trigger the majority of inflammatory and apoptotic effects, although TNFR2 has recently been shown to play more of a role in signal transduction than was initially thought. TNF-alpha is responsible for the induction of apoptosis in certain cell types, where it plays a pivotal role in the induction of cytotoxicity, killing of neoplastic cells and deletion of autoreactive T-cell clones. This cytokine, and in particular, its overproduction, has been implicated in the pathogenesis of a variety of immunologically mediated inflammatory diseases, including endotoxic shock, inflammatory bowel disease (IBD), multiple sclerosis (MS) and rheumatoid arthritis (RA). Currently, there is an intense effort underway to regulate TNF-alpha production and activity, in order to treat diseases where TNF-alpha is thought to be pathologically indicated. To achieve this goal, the pharmaceutical industry is currently pursuing a 2 pronged strategy: a) testing biological agents such as antibodies against TNF-alpha or soluble TNF-alpha receptor constructs, and b) identifying small molecular inhibitors directed against targets such as phosphodiesterase-IV (PDE-IV) and TNF-alpha converting enzyme (TACE), a subgroup of the matrix metalloproteinases (MMP). The main difficulties in the clinical implementation of the biological agents are: development of immunogenicity, lack of oral availability and the high cost of production. The currently available small molecular compounds exhibit poor bio-availability and low selectivity, resulting in unacceptable side effects and a low therapeutic index. Despite these hurdles, numerous companies are actively pursuing agents that inhibit TNF-alpha.
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PMID:AntiTNF-alpha agents in the treatment of inflammation. 1599 32

D-hormone [1,25(OH)2 D3] is an important immune system regulator that has been shown to inhibit development of autoimmune diseases including experimental inflammatory bowel disease (IBD), rheumatoid arthritis (RA), multiple sclerosis (MS), and type 1 diabetes. Paradoxically, other immune mediated diseases (experimental asthma) and immunity to infectious organisms were not found to be affected by D-hormone treatment. The effectiveness of D-hormone treatment of autoimmune diseases is due to inhibition of the development and function of Th1 cells and the induction of other Th cells including Th2 cells. We report results of microarray analysis of colons from D-hormone treated mice with experimental IBD. Two hundred thirty-nine genes were inhibited and 298 genes were upregulated in the colon by D-hormone treatment of mice with IBD. Of interest was the D-hormone mediated inhibition of 3 tumor necrosis factor-alpha (TNF-alpha, lipopolysaccharide-induced TNF-alpha factor, and TNF receptor) related genes in the colon. It is likely that the effectiveness of D-hormone treatment of experimental autoimmunity is due in part to the inhibition of the TNF family of genes. D-hormone is a selective regulator of the immune system, and the outcome of D-hormone treatment depends on the nature (infectious disease, asthma, autoimmune disease, etc.) of the immune response.
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PMID:D-hormone and the immune system. 1614 46

We report a case of heart failure after infusion of Remicade (infliximab) in a patient without heart insufficiency. The patient, a 25-year-old woman with inflammatory bowel disease, developed new-onset heart failure after receiving TNF antagonist therapy. After the treatment was discontinued and heart failure therapy was started, the patient improved significantly. The U.S. Food and Drug Administration has published 47 case reports of heart failure after therapy with a tumor necrosis factor antagonist, where 38 patients developed new-onset heart failure and 9 patients experienced heart failure exacerbation. There are no published reports of heart failure after TNF antagonist therapy in the Danish literature.
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PMID:[Dilated cardiomyopathy as a side effect of treatment with infliximab]. 1621 21

Despite all of the advances in our understanding of the pathophysiology of inflammatory bowel disease (IBD), we still do not know its cause. Some of the most recently available data are discussed in this review; however, this field is changing rapidly and it is increasingly becoming accepted that immunogenetics play an important role in the predisposition, modulation and perpetuation of IBD. The role of intestinal milieu, and enteric flora in particular, appears to be of greater significance than previously thought. This complex interplay of genetic, microbial and environmental factors culminates in a sustained activation of the mucosal immune and non-immune response, probably facilitated by defects in the intestinal epithelial barrier and mucosal immune system, resulting in active inflammation and tissue destruction. Under normal situations, the intestinal mucosa is in a state of 'controlled' inflammation regulated by a delicate balance of proinflammatory (tumour necrosis factor [TNF]-alpha, interferon [IFN]-gamma, interleukin [IL]-1, IL-6, IL-12) and anti-inflammatory cytokines (IL-4, IL-10, IL-11). The mucosal immune system is the central effector of intestinal inflammation and injury, with cytokines playing a central role in modulating inflammation. Cytokines may, therefore, be a logical target for IBD therapy using specific cytokine inhibitors. Biotechnology agents targeted against TNF, leukocyte adhesion, T-helper cell (T(h))-1 polarisation, T-cell activation or nuclear factor (NF)-kappaB, and other miscellaneous therapies are being evaluated as potential therapies for IBD. In this context, infliximab is currently the only biologic agent approved for the treatment of inflammatory and fistulising Crohn's disease. Other anti-TNF biologic agents have emerged, including CDP 571, certolizumab pegol (CDP 870), etanercept, onercept and adalimumab. However, ongoing research continues to generate new biologic agents targeted at specific pathogenic mechanisms involved in the inflammatory process. Lymphocyte-endothelial interactions mediated by adhesion molecules are important in leukocyte migration and recruitment to sites of inflammation, and selective blockade of these adhesion molecules is a novel and promising strategy to treat Crohn's disease. Therapeutic agents that inhibit leukocyte trafficking include natalizumab, MLN-02 and alicaforsen (ISIS 2302). Other agents being investigated for the treatment of Crohn's disease include inhibitors of T-cell activation, peroxisome proliferator-activated receptors, proinflammatory cytokine receptors and T(h)1 polarisation, and growth hormone and growth factors. Agents being investigated for treatment of ulcerative colitis include many of those mentioned for Crohn's disease. More controlled clinical trials are currently being conducted, exploring the safety and efficacy of old and new biologic agents, and the search certainly will open new and exciting perspectives on the development of therapies for IBD.
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PMID:Biologic therapy for inflammatory bowel disease. 1626 94

Single nucleotide polymorphisms (SNPs) play a central role in the identification of susceptibility genes for common diseases. Recent empirical studies on human genome have revealed block-like structures, and each block contains a set of haplotype tagging SNPs (htSNPs) that capture a large fraction of the haplotype diversity. Herein, we present an innovative sparse marker extension tree (SMET) algorithm to select optimal htSNP set(s). SMET reduces the search space considerably (compared to full enumeration strategy), and therefore improves computing efficiency. We tested this algorithm on several datasets at three different genomic scales: (1) gene-wide (NOS3, CRP, IL6 PPARA, and TNF), (2) region-wide (a Whitehead Institute inflammatory bowel disease dataset and a UK Graves' disease dataset), and (3) chromosome-wide (chromosome 22) levels. SMET offers geneticists with greater flexibilities in SNP tagging than lossless methods with adjustable haplotype diversity coverage (phi). In simulation studies, we found that (1) an initial sample size of 50 individuals (100 chromosomes) or more is needed for htSNP selection; (2) the SNP tagging strategy is considerably more efficient when the underlying block structure is taken into account; and (3) htSNP sets at 80-90% phi are more cost-effective than the lossless sets in term of relative power, relative risk ratio estimation, and genotyping efforts. Our study suggests that the novel SMET algorithm is a valuable tool for association tests.
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PMID:A sparse marker extension tree algorithm for selecting the best set of haplotype tagging single nucleotide polymorphisms. 1629 99

Psoriasis is an inflammatory skin disease that affects 1-3% of the European population. Chronic plaque psoriasis, the commonest form of the condition - affecting the majority of patients - usually manifests as red, heavily scaled plaques on elbows, knees, scalp and lower back, but any skin surface may be affected. Psoriasis is associated with an inflammatory sero-negative arthritis, namely "psoriatic arthritis", in approximately 15%of patients with psoriasis and occurs more commonly in people with inflammatory bowel disease such as patients with Crohn's disease. Several studies have demonstrated the role of genetic predisposition, innate and adaptive immunity in the pathogenesis of psoriasis. There is considerable evidence that innate immunity and specifically a dysregulation of the innate immune response is central to the development of psoriasis. The role of TNFalpha is particularly intriguing. The evidence includes further observations that a variety of anti-TNF approaches such as monoclonal antibodies and fusion proteins of soluble TNF receptors are effective therapies both in psoriasis and psoriatic arthritis. In this review, in addition to pathogenetic aspects, some preliminary guidelines for the use of anti-TNFalpha therapy in patients with psoriasis and psoriatic arthritis will be discussed.
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PMID:Psoriasis and psoriatic arthritis: immunological aspects and therapeutic guidelines. 1646 29

Inflammatory bowel disease (IBD) still presents major challenges to the understanding of its cause, mechanisms of inflammation, and therapeutic choices to control the damaged tissue. Both types of IBD, ulcerative colitis and Crohn's disease, have been known and investigated for over half century but neither one is fully understood nor can be satisfactorily managed. While many gaps in our knowledge still exist, the last two decades have witnessed an unprecedented progress not only in the etiology but mainly in the mechanisms underlying the chronic inflammatory response. The pattern of IBD epidemiology has drastically changed since World War II, with an increased frequency in countries that have adopted a ''westernized'' life style. A parallel and important phenomenon is the continuous drop in age of onset in children. Unfortunately, only few epidemiological clues are available, with the exception of smoking and diet. What in smoking alters the course of IBD is still a mystery and which, among thousands of additives, could represent a risk factor will remain unknown for the foreseeable future. The current emphasis on the study of the enteric flora as the source of potential antigens against which the mucosal immune system reacts appear well justified. The data from animal models appears particularly convincing. Thus, after decades of relying almost exclusively on patient-derived information, numerous animal models are generating precious new information on IBD pathogenesis. In experimental IBD the genetic background of the animal markedly influences the course of the disease, and the same is probably true in humans. The identification of NOD2 as the first mutated gene associated with a subgroup of Crohn's disease patients is the first evidence that genetics are pointing to the right direction for understanding how the environment interacts with genes to cause IBD. For many years immunology has been the main source of scientific information on mechanisms of IBD. Cytokines, chemokines and other soluble factors dominate immunological studies aimed at understanding how different anti-inflammatory and pro-inflammatory mediators are improperly regulated and how immune imbalance can be restored. The extent to which T-cells live or die is also a key determinant of chronicity. In addition to classical immune cells, epithelial, endothelial, mesenchymal and nerve cells are slowly gaining more importance in IBD pathogenesis, as they contribute to the ultimate fate of tissue damage. Medical and surgical therapies are vastly better now that they were only a couple of decades ago, but they are still far from satisfactory. Steroid and aminosalicylates are still the most common drugs after 60 years of use, and it is time to renovate our therapeutic approach to a more effective one. The value of biologicals has been highlighted by the recent success of anti-TNF therapy. Timing of therapy must also change. The concept of the step-by-step approach is slowly fading away, and the idea of an ''all-out'' approach with multiple concomitant drugs early in the disease is gaining credibility. New reports on early aggressive therapies, and the demonstration that early and late experimental IBD are caused by different mechanisms are changing the way we think about managing IBD. Both ulcerative colitis and Crohn's disease will continue to challenge the medical establishment for year to come, but the possibility that IBD can be conquered is more realistic now that never before.
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PMID:Inflammatory bowel disease. Current concepts of pathogenesis and implications for therapy. 1649 Oct 45


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