Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0010346 (Crohn's disease)
 21,615 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Crohn's disease (CD) is a condition characterized by excessive numbers of activated T cells in the mucosa. We investigated whether a defect in apoptosis could prolong T cell survival and contribute to their accumulation in the mucosa. Apoptotic, Bcl-2+, and Bax+ cells in tissue sections were detected by the TUNEL method and immunohistochemistry. T cell apoptosis was induced by IL-2 deprivation, Fas Ag ligation, and exposure to TNF-alpha and nitric oxide. TUNEL+ leukocytes were few in control, CD, and ulcerative colitis (UC) mucosa, with occasional CD68+ and myeloperoxidase+, but no CD45RO+, apoptotic cells. Compared with control and UC, CD T cells grew remarkably more in response to IL-2 and were significantly more resistant to IL-2 deprivation-induced apoptosis. CD T cells were also more resistant to Fas- and nitric oxide-mediated apoptosis, whereas TNF-alpha failed to induce cell death in all groups. Compared with control, CD mucosa contained similar numbers of Bcl-2+, but fewer Bax+, cells, while UC mucosa contained fewer Bcl-2+, but more Bax+, cells. Hence, the Bcl-2/Bax ratio was significantly higher in CD and lower in UC. These results indicate that CD may represent a disorder where the rate of T cell proliferation exceeds that of cell death. Insufficient T cell apoptosis may interfere with clonal deletion and maintenance of tolerance, and result in inappropriate T cell accumulation contributing to chronic inflammation.
 ...
PMID:Resistance of Crohn's disease T cells to multiple apoptotic signals is associated with a Bcl-2/Bax mucosal imbalance. 1039 8

This study reports the clinical benefit and safety of the murine chimeric anti-tumor necrosis factor (TNF)-alpha monoclonal antibody, infliximab, in the treatment of patients who developed findings compatible with Crohn's disease after undergoing colectomy with ileal-pouch anal anastomosis (IPAA) for an original diagnosis of ulcerative colitis. Medical records of 7 patients with Crohn's disease and an IPAA treated with infliximab were reviewed. Clinical response was classified as complete response, partial response, and no response. Concurrent treatment with immune modifier agents and/or antibiotics was recorded. Seven patients with active inflammatory or fistulizing Crohn's disease and an IPAA performed for diagnosis of ulcerative colitis were treated with infliximab after they had no response to conventional therapies. Patients received 1-4 infliximab infusions at a dose of 5 mg/kg. All patients improved clinically. Six patients had a complete response, and 1 had a partial response. Four of the 5 patients with complex perianal and fistulizing disease had closure of all fistula tracts, and 1 patient improved temporarily. Six of the 7 patients underwent concurrent treatment with immune modifier drugs. One patient had myalgias and malaise after the first infliximab infusion and flu-like symptoms after the second one. No other adverse effects were observed. This case series demonstrates that the murine chimeric anti-TNF-alpha monoclonal antibody, infliximab, can be used successfully to treat patients with Crohn's disease involving an IPAA who are refractory to conventional therapies.
 ...
PMID:Successful management of Crohn's disease of the ileoanal pouch with infliximab. 1289 80

The aetiology of inflammatory bowel disease remains unclear. Local mediators such as arachidonic acid metabolites and peptide mediators (cytokines) appear to contribute to the disease process. The successful administration of neutralizing antibodies against TNF-alpha has confirmed a pathophysiological role for this cytokine in Crohn's disease. Established therapy of inflammatory bowel disease with 5-aminosalicylic acid compounds has been shown to reduce local leukotriene B4 formation by inhibiting lipoxygenases. This therapeutic mechanism formed one rationale for examining the effect of n-3 fatty acids, which also inhibit leukotriene B4 formation, on the course of these diseases. In the first study, published in 1989, we found no beneficial effects of n-3 fatty acids in patients with Crohn's disease; however, there was clinical improvement, just falling short of significance, in patients with ulcerative colitis. Since then two uncontrolled and five controlled studies have further investigated the therapeutic effect of n-3 fatty acids in patients with ulcerative colitis. The size of the patient population in the controlled studies ranged from 10 to 96 patients in the largest study. Two of these studies showed a significant improvement in clinical activity and a steroid-sparing effect, respectively. Another study found only a trend towards improvement and one trial, which also included a treatment group receiving evening primrose oil, found no beneficial effect in the 16 patients receiving n-3 fatty acids. A large, 2 year trial of n-3 fatty acids in patients with ulcerative colitis off steroids, which was recently completed at the Universities of Munich and Mainz, showed a delay of the first episode of relapse, but no reduction in the cumulative relapse rate at 2 years. Controversial results have been published for Crohn's disease. A new enteric-coated formulation reportedly increased the proportion of patients in remission where as another trial using a conventional preparation found no significant effect.
 ...
PMID:Lipid treatment of inflammatory bowel disease. 1045 41

The role of TNF-alpha in the mucosal inflammation of Crohn's disease has been demonstrated by the prolonged clinical responses and/or remissions among patients receiving i.v. infusion of anti-TNF-alpha. A correlation between TNF-alpha and elevated IFN-gamma production is suggested by the reduction in the number of IFN-gamma producing lamina propria mononuclear cells (LPMC) found in colonic biopsies from anti-TNF-alpha-treated patients. The aim of this study was to define the mechanism of TNF-alpha-augmented mucosal T cell IFN-gamma production. In this paper we present evidence that cultured LPMC secrete a factor which acts on preactivated T cells in concert with TNF-alpha to augment IFN-gamma production. This activity is independent of IL-12 and IL-18, the well-documented potentiators of IFN-gamma expression, and is not produced by PBMC. Peripheral blood PHA-activated T cells incubated in supernatants from LPMC became responsive to TNF-alpha by increasing IFN-gamma output upon stimulation. These results are consistent with a model in which LPMC, but not PBMC, release an unidentified substance when cultured in vitro with low dose IL-2. This substance can act on preactivated peripheral T cells, as well as on lamina propria T cells, conditioning them to respond to TNF-alpha by increased IFN-gamma secretion upon stimulation. Expression of this factor in the gut mucosa could contribute to up-regulation of the Th1 response in the presence of TNF-alpha, and could be important for mucosal immunoregulation.
 ...
PMID:A soluble factor produced by lamina propria mononuclear cells is required for TNF-alpha enhancement of IFN-gamma production by T cells. 1051 Mar 66

With recent elucidation of pathophysiology and inflammatory process on inflammatory bowel disease(IBD), new drugs and treatments for IBD have developed rapidly. In addition to it, mechanisms of salicylazosulfapyridine, 5-aminosalicylic acid, and glucocorticoid have been clarified at molecular levels as cell transcription factors of NF-kappa B. This paper described the following recent therapy performed in IBD patients; 1)leukocytapheresis by G-column, LCAP and centrifugal separator. 2)cytokine and anti-cytokine therapy with anti-TNF-alpha chimeric monoclonal antibody and IL-10 for treatment of Crohn' disease. 3)therapy with antisense oligonucleotide against ICAM-1 in Crohn's disease, and against p65 subunit of NF-kappa B in TNBS induced colitis in mice. 4)therapy modulating receptor function of target cells. 5)therapy with antibody against cell adhesion molecules. 6)radical scavenger therapy with lipo-SOD. And, 7)treatment with low molecular heparin.
 ...
PMID:[Present states of development in new drugs and treatment of inflammatory bowel disease]. 1057 18

Crohn's disease (CD) is a multifactorial disease with genetic heterogeneity. TNF-alpha plays a key role in the development of the mucosal lesions. The aim of our work was to study a single base pair polymorphism located in the promoter region of TNF gene, in a large population of CD patients with well defined phenotypes. One hundred and ninety-three patients with CD and 98 ethnically matched controls were studied. The -308 single base pair polymorphism of TNF gene was studied using an allele-specific polymerase chain reaction. Genotype and allelic frequencies were compared between patients and controls and between subgroups of patients defined by sex, age at diagnosis, familial history, location of disease, type of disease, extra-intestinal manifestations, and response to steroid treatment. In 29 patients a measure of TNF-alpha production by colonic biopsies was performed. The frequency of the allele TNF2 as well as the proportion of carriers of the allele TNF2 were slightly but not significantly lower in CD than in controls (11.9% versus 14.8% and 21.5% versus 27.6%, respectively). A more prominent difference in frequencies of allele TNF2 and in proportions of TNF2 carriers was found when comparing subgroups of patients. The frequency of allele TNF2 was significantly higher in steroid-dependent than in non-steroid-dependent disease (28.1% versus 10.3%; Delta = 17.8%, 95% confidence interval (CI) = 6.3-29.5%, P = 0.0027) and tended to be higher in colonic than in small bowel disease and in fistulizing than in stricturing disease. Furthermore, TNF2 carriers tended to be more frequent in patients with steroid-dependent than non-steroid-dependent disease (43.8% versus 19.3%; Delta = 24.5%, 95% CI = 3.6-45.4%, P = 0.022), in patients with fistulizing than stricturing disease (26.5% versus 9.6%; Delta = 16.9%, 95% CI = 1. 1-32.6%, P = 0.036), and in patients with colonic than small bowel disease (26.5% versus 11.1%; Delta = 15.4%, 95% CI = -0.8-31.6%, P = 0.063). Finally, patients carrying at least one copy of allele 2 were found to produce slightly more TNF-alpha at the colonic level. The -308 TNF gene polymorphism may have a slight influence on the behaviour of CD. The carriage of allele 2 may favour steroid-dependent disease and to a lesser extent fistulizing and colonic disease, possibly secondary to a more intense TNF-alpha-driven inflammatory reaction at the mucosal level.
 ...
PMID:Tumour necrosis factor (TNF) gene polymorphism in Crohn's disease (CD): influence on disease behaviour? 1060 65

Crohn's disease and ulcerative colitis are caused by excessive immune reactivity in the gut wall. Analysis of the type of immune responses ongoing in diseased gut has revealed important features which suggest that these conditions are different. In Crohn's disease tissue there is considerable evidence for an ongoing T helper cell type 1 response, with excess interleukin-12, interferon-gamma and TNF-alpha. There is circumstantial evidence in patients that this response is directed against the normal bacterial flora and definitive evidence in mouse models that T cell responses to the flora cause gut disease. In ulcerative colitis, the role of tissue damaging T cell responses in the gut mucosa is much less clear and there is more evidence that the lesion is owing to antibody-mediated hypersensitivity. Although different types of immune reactions initiate tissue injury in both Crohn's disease and ulcerative colitis, the downstream events which actually damage the tissue are the same in each condition. Elevated cytokine concentrations in the mucosa lead to the production of excess matrix degrading enzymes by gut fibroblasts, loss of mucosal integrity and ulceration. The same process also leads to an increased production of epithelial growth factors such as KGF Keratinocyte Growth Factor by gut fibroblasts and produces the crypt cell hyperplasia characteristic of all gut inflammatory conditions.
 ...
PMID:Recent developments in the immunology of inflammatory bowel disease. 1063 69

CD4+ T-lymphocytes have a central role in the pathogenesis of Crohn's disease. The activation and proliferation of T-lymphocytes following stimulation by antigen-presenting cells is controlled by regulatory cytokines (i.e. IL-10) and by induction of programmed cell death. Tissue damage as a result of T-lymphocyte-mediated inflammation is mediated by pro-inflammatory cytokines, including TNF-alpha. Novel immunodulatory strategies in Crohn's disease are based on these principles, and it has been demonstrated that neutralization of TNF-alpha by administration monoclonal antibodies as well as administration of recombinant human IL-10 have therapeutic activity in Crohn's disease. The current status of these new therapies as well as future developments are discussed.
 ...
PMID:Immunotherapy of Crohn's disease. 1063 71

Assessment of disease activity in inflammatory bowel disease (IBD), i.e., ulcerative colitis (UC) and Crohn's disease (CD), is done using clinical parameters and various biological disease markers. Ideally, a disease marker must: be able to identify individuals at risk of a given disorder, be disease specific, mirror the disease activity and, finally, be easily applicable for routine clinical purposes. However, no such disease markers have yet been identified for IBD. In this article, classical disease markers including erythrocyte sedimentation rate, acute phase proteins (especially orosomucoid and CRP), leukocyte and platelet counts, albumin, neopterin, and beta2-microglobulin will be reviewed together with emerging disease markers such as antibodies of the ANCA/ASCA type, cytokines (e.g., IL-1, IL-2Ralpha, IL-6, IL-8, TNF-alpha, and TNF-alpha receptors) and with various adhesion molecules. It is concluded that none of the pertinent laboratory surrogate markers of disease activity in IBD are specific or sensitive enough to replace basic clinical observation such as the number of daily bowel movements, general well-being, and other parameters in parallel. Further studies are highly warranted to identify and assess the clinical importance and applicability of new laboratory markers for the diagnosis or the disease activity of IBD.
 ...
PMID:Established and emerging biological activity markers of inflammatory bowel disease. 1092 11

The medical treatment of inflammatory bowel disease is dependent on disease activity and bowel involvement. Severe Crohn's disease and ulcerative colitis are primarily treated with corticosteroids. Alternatively, if inflammation is localised in the right colon and ileum, budesonide may be used in view of its low systemic side effects. In distal colitis and perianal disease, topical therapy with steroids is very effective. In moderate disease preparations containing 5-aminosalicylate (5-ASA) may be used. The latter are highly effective applied locally in distal disease. Steroids should be tapered down and whenever possible not used to maintain remission. In patients with ulcerative colitis, 5-ASA is effective in maintaining remission, whereas this medication plays only a limited role in Crohn's disease. Refractory disease or patients with multiple flare-ups should be treated with azathioprine. Infliximab, an anti-TNF-alpha antibody, is a potent therapy for fistulising Crohn's disease or steroid-refractory disease. Other approved and experimental treatments are discussed.
 ...
PMID:[Drug treatment of chronic inflammatory bowel diseases: current status and prospects]. 1071 13


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>