Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021390 (inflammatory bowel disease)
 23,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The better understanding of the mechanisms of inflammatory bowel disease has driven our progress into the development of new biological therapies targeting specific molecules. Anti-TNF-alpha biologic compounds have shown great efficacy particularly in Crohn's disease. Infliximab (an IgG1 mouse/human chimeric monoclonal anti-TNF-alpha antibody fragment) is the most efficacious compound in induction and maintenance therapy of active and fistulizing Crohn's disease, being at present the only biological compound approved for therapy, but with the limit of the immunogenicity; CDP-571 (a humanized anti-TNF-alpha antibody) and CDP-870 (a PEGylated anti-TNF-alpha antibody) are less immunogenic, showed some efficacy in induction therapy in Crohn's disease but a rapid loss of response in maintenance therapy. Etanercept and onercept (soluble human recombinant TNF-alpha receptors fusion proteins) seem not to be efficacious in Crohn's disease demonstrating no class-effect for anti-TNF-alpha compounds. In preliminary study, adalimumab (an IgG1 humanized monoclonal anti-TNF-alpha antibody) offers good perspective of efficacy and safety also in infliximab-resistant or allergic patients. Inhibition of lymphocyte trafficking to the gut, through anti-adhesion molecules specific therapies (natalizumab, MLN-02, alicaforsen), has shown promising results: unfortunately, natalizumab, the most effective drug of this class, has recently been suspected to favour serious neurological complications. Other biologic therapies are under evaluation but at present seem to be less promising than infliximab; they consist of antiinflammatory cytokines, inhibitors of proinflammatory cytokines, hormones and growth factors: anti-IL12-antibody, interferon-alpha, interferon-beta, G-CSF, GM-CSF, EGF, growth hormone, anti-interferon-gamma, anti-IL-18, anti-IL-2-receptor and anti-CD3 antibodies. The evaluation of other biological drugs has been suspended for severe side effects as happened for anti-CD40L antibody causing thromboembolism and anti-CD4 antibody causing ly.mphopenia. Other compounds as IL-10 and IL-11 have been proven to be ineffective even if an oral formulation of IL-11 is under evaluation. Among the MAP kinases inhibitors BIRB-796 and RDP58 showed to be ineffective while CNI-1493 is under evaluation. The effort in identifying specific patients features predicting therapy response and the possible combination of different biological therapies represent undoubtedly a very promising perspective. Aim of this article is to review the biological compounds and their efficacy in IBD.
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PMID:Biological therapies for inflammatory bowel disease: research drives clinics. 1684 27

Inflammatory bowel disease (IBD) is a common condition in cats characterised by infiltration of inflammatory cells into the intestinal mucosa. In this study, real-time reverse transcriptase polymerase chain reaction (RT-PCR) was used to quantify cytokine messenger RNA (mRNA) expression in intestinal biopsies from cats. Biopsies were collected from seven cats with chronic diarrhoea and histologically confirmed IBD, five cats with chronic diarrhoea due to non-IBD gastrointestinal (GI) disease, and nine clinically normal cats with or without subclinical inflammatory changes in small intestine. Real-time RT-PCR was developed for quantification of mRNA encoding interleukin (IL)-2, IL-4, IL-5, IL-6, IL-10, IL-12 (p35 and p40), IL-18, tumour necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) and transforming growth factor-beta (TGF-beta). Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as a 'housekeeper' gene. All real-time PCR efficiencies were>90% (range 90.4-102%) with correlation coefficients >0.99 (range 0.998-1). The results of the study were analyzed on the basis of either clinical presentation or histopathological evidence of intestinal inflammation. The former analysis showed that mRNA encoding IL-10 and TGF-beta (immunoregulatory cytokines), and IL-6, IL-18, TNF-alpha and IL-12 p40 (Th1 and pro-inflammatory cytokines) was significantly higher in clinically normal cats and cats with IBD when compared to cats with other GI diseases. IL-5 mRNA was significantly higher in cats with IBD compared to clinically normal cats. IL-2 mRNA was significantly lower in cats with non-IBD GI disease than in clinically normal cats. Analysis on the basis of histopathological change revealed that cats with intestinal inflammation had significantly more transcription of genes encoding IL-6, IL-10, IL-12p40, TNF-alpha and TGF-beta than those with normal intestinal morphology. The results suggest that immune dysregulation plays a role in feline IBD and that IBD in cats has a complicated pathogenesis with both pro-inflammatory and immunoregulatory features.
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PMID:Measurement of cytokine mRNA expression in intestinal biopsies of cats with inflammatory enteropathy using quantitative real-time RT-PCR. 1687 76

IL-15, a T-cell growth factor, has been shown to be increased in inflammatory bowel disease (IBD). It has been suggested that neutralization of IL-15 could protect from T cell-dependent autoimmune inflammation. On the other hand, an anti-apoptotic effect of IL-15 has been demonstrated in kidney epithelial cells during nephritis. We therefore tested the role of IL-15 in two different experimental models of colitis in vivo, and in models of intestinal epithelial cell (IEC) apoptosis in vitro. IL-15 blockade in chronic dextran sulphate sodium-induced colitis resulted in aggravation of the disease with a significantly 2.1-fold increased epithelial damage score compared to controls. TUNEL staining clearly revealed increased apoptosis. IL-6, TNF and IFN-gamma secretion by mesenteric lymph node cells were increased. In the T cell-dependent SCID transfer model of colitis IL-15 neutralization reduced the inflammatory infiltration and proinflammatory cytokine production. Despite that, the intestinal epithelial damage was not reduced. In vitro, IL-15 pre-incubation prevented up to 75% of CH11 antibody-induced apoptosis in SW-480 cells and reduced caspase-3 activity. According to this, endogenously produced IL-15 in chronic colitis does not only act as a proinflammatory cytokine but has at the same time the potential to reduce mucosal damage by preventing IEC apoptosis.
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PMID:IL-15 protects intestinal epithelial cells. 1698 Nov 78

The role of gammadelta T cells in inflammatory bowel disease (IBD) is still controversial. Although gammadelta T cells induce IBD in immunodeficient animals, others suggest a protective role of gammadelta T cells. Therefore, this study was conducted in order to elucidate the effect of gammadelta T cell depletion/deficiency on different IBD animal models. Mice depleted of or deficient in gammadelta T cells were exposed to dextran sodium sulfate (DSS) in order to induce colitis. In addition, gammadelta T cells were depleted in mice with terminal ileitis (TNFDeltaARE) or colitis due to interleukin 2 deficiency (IL-2 ko). Finally, DSS-induced colitis was studied in mice deficient in interferon gamma (IFN-gamma ko) upon gammadelta T cell depletion. Depletion of gammadelta T cells aggravated DSS-induced colitis and terminal ileitis of TNFDeltaARE mice. Exacerbated DSS-induced colitis was also found in gammadelta T cell-deficient mice. IL-2 ko mice showed increased mortality upon early (starting at 4 wk of age) but not late depletion (starting at 8 wk of age). Early gammadelta T cell depletion or deficiency resulted in increased IFN-gamma production by both lamina propria lymphocytes and splenocytes in every model investigated herein. In IFN-gamma ko mice, gammadelta T cell depletion did not affect the development and course of DSS-induced colitis. The protective effect of gammadelta T cells in IBD was confirmed in various IBD animal models. Particularly, during the early phase of intestinal inflammation, gammadelta T cells appear to be important. The mechanism seems to involve the control of IFN-gamma production and epithelial regeneration.
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PMID:Aggravation of intestinal inflammation by depletion/deficiency of gammadelta T cells in different types of IBD animal models. 1704 Oct 3

In the present study we have characterized T cell-driven immune function in mice that are genetically deficient in PKC theta. In response to simple immunologic stimulation invoked by in vivo T cell receptor (TCR) cross-linking, these mice showed significantly depressed plasma cytokine levels for IL-2, IL-4, IFNgamma, and TNFalpha compared to wild-type (WT) mice. In parallel, spleen mRNA levels for these cytokines were reduced, and NF-kappaB activation was also reduced in PKC theta knockouts (KO). Injection of allogeneic cells into the footpad of PKC theta deficient mice provoked a significantly diminished local T cell response compared to WT mice similarly challenged. Unlike comparable cells from wild type mice, CD45RBhi T cells harvested from PKC theta deficient mice failed to induce colitis in the SCID-CD45RB cell transfer model of IBD. In another T cell-dependent model of inflammatory disease, PKC theta deficient animals developed far less severe neurologic signs and reduced spinal cord inflammatory cell infiltrate compared to WT controls in the MOG-induced EAE model. A fundamental role for PKC theta in T cell activation and in the development of T cell-mediated inflammatory diseases is indicated by these results.
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PMID:Mice deficient in PKC theta demonstrate impaired in vivo T cell activation and protection from T cell-mediated inflammatory diseases. 1706 26

Inflammatory bowel disease (IBD) represents a spectrum of diseases in which inflammation leads to acute and chronic gut injury. It is a growing health issue for which no cure exists. The pathogenesis is multifactorial with links to infectious and environmental events that trigger disease in genetically predisposed individuals. Treatment of the two major forms of IBD, Crohn's disease and ulcerative colitis, involves the reduction of inflammation with toxic immunosuppressive drugs or blocking of the pro-inflammatory effects of tumour necrosis factor-alpha (TNF-alpha) with antibodies. Here, we show that the oral administration of transgenic low-alkaloid tobacco expressing the contra-inflammatory cytokine human interleukin-10 (hIL-10) reduces the severity of colitis by down-regulating TNF-alpha expression directly at the sites of inflammation in IBD-susceptible IL-10(-/-) mice. hIL-10 expressed in plants is biologically active and displays resistance to gastrointestinal degradation. Dietary supplementation with plant tissue delivering up to 9 microg of hIL-10 daily for 4 weeks was well tolerated by treated mice. Gut histology was significantly improved relative to controls (P = 0.002), and was correlated with a decrease in small bowel TNF-alpha mRNA levels and an increase in IL-2 and IL-1beta mRNA levels. Transgenic plants expressing IL-10 to directly attenuate TNF-alpha expression at sites of inflammation in the gut may become a useful new approach in the luminal therapy of IBD.
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PMID:Therapeutic effectiveness of orally administered transgenic low-alkaloid tobacco expressing human interleukin-10 in a mouse model of colitis. 1720 56

Previous studies have suggested that intestinal epithelial cells (IECs) have the capacity to function as nonprofessional antigen presenting cells that in the normal state preferentially activate CD8+ T cells. However, under pathological conditions, such as those found in inflammatory bowel disease (IBD), persistent activation of CD4+ T cells is seen. The aim of this study was to determine whether the IBD IECs contribute to CD4+ T cell activation. Freshly isolated human IECs were obtained from surgical specimens of patients with or without IBD and cocultured with autologous or allogeneic peripheral blood T lymphocytes. Cocultures of normal T cells and IECs derived from IBD patients resulted in the preferential activation of CD4+ T cell proliferation that was associated with significant IFN-gamma, but not IL-2, secretion. Cytokine secretion and CD4+ T cell proliferation was inhibited by pretreatment of the IBD IECs with the anti-DR MAb L243. In contrast, normal IECs stimulated the proliferation and cytokine secretion by CD4+ T cells to a significantly lesser degree than IBD IECs. Furthermore, blockade of human leukocyte antigen-DR had a lesser effect in the normal IEC-CD4+ T cell cocultures. We conclude that IECs can contribute to the ongoing CD4+ T cell activation seen in IBD. We suggest that the apparent differences between the secreted levels of IFN-gamma indicate that it may play a dual role in intestinal homeostasis, in which low levels contribute to physiological inflammation whereas higher levels are associated with an uncontrolled inflammatory state.
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PMID:Intestinal epithelial cells from inflammatory bowel disease patients preferentially stimulate CD4+ T cells to proliferate and secrete interferon-gamma. 1734 51

Various animal models showed that peroxisome proliferator-activated receptor (PPAR)gamma agonists, when given as a gavage shortly preceding colitis induction, protect against inflammatory bowel disease (IBD). We have examined the effects of 16 days rosiglitazone treatment via the diet prior to dextran sodium sulphate (DSS)-induced colitis in mice. After 7 days DSS in the drinking water, rosiglitazone-fed mice had lost significantly more weight than control mice. Rosiglitazone-treated mice had more diarrhea, weight of colon and spleen were increased, and length of colon was decreased. Histology showed that rosiglitazone-treated mice had more severe colitis, mainly caused by more ulceration, crypt loss, and edema. Immunofluorescence showed a loss of tight junction structure Zonula Occludens protein 1 (ZO-1) in colons of rosiglitazone-treated mice as compared to control mice. Also, serum amyloid P component (SAP) concentrations in plasma were increased. However, concentrations of tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma in colon homogenates, and TNF-alpha in spleen homogenates were significantly decreased, whereas interleukin (IL)-10 in spleen homogenates was increased. Other cytokines (IL-2, IL-4, IL-6, IL-12p70 and monocyte chemotactic protein (MCP)-1) and myeloperoxidase (MPO) concentrations showed no differences. In conclusion, 16 days pretreatment with rosiglitazone impaired DSS-induced colitis in mice.
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PMID:The PPARgamma agonist rosiglitazone impairs colonic inflammation in mice with experimental colitis. 1751 Aug 6

Our aim was to assess anti-inflammatory effects on the peripheral blood of subjects with inflammatory bowel disease (IBD) who consumed probiotic yogurt for 1 month. We studied 20 healthy controls and 20 subjects with IBD, 15 of whom had Crohn's disease and five with ulcerative colitis. All the subjects consumed Lactobacillus rhamnosus GR-1 and L. reuteri RC-14 supplemented yogurt for 30 days. The presence of putative regulatory T (T(reg)) cells (CD4(+) CD25(high)) and cytokines in T cells, monocytes and dendritic cells (DC) was determined by flow cytometry from peripheral blood before and after treatment, with or without ex vivo stimulation. Serum and faecal cytokine concentrations were determined by enzyme-linked immunosorbent assays. The proportion of CD4(+) CD25(high) T cells increased significantly (P = 0.007) in IBD patients, mean (95% confidence interval: CI) 0.84% (95% CI 0.55-1.12) before and 1.25% (95% CI 0.97-1.54) after treatment, but non-significantly in controls. The basal proportion of tumour necrosis factor (TNF)-alpha(+)/interleukin (IL)-12(+) monocytes and myeloid DC decreased in both subject groups, but of stimulated cells only in IBD patients. Also serum IL-12 concentrations and proportions of IL-2(+) and CD69(+) T cells from stimulated cells decreased in IBD patients. The increase in CD4(+) CD25(high) T cells correlated with the decrease in the percentage of TNF-alpha- or IL-12-producing monocytes and DC. The effect of the probiotic yogurt was confirmed by a follow-up study in which subjects consumed the yogurt without the probiotic organisms. Probiotic yogurt intake was associated with significant anti-inflammatory effects that paralleled the expansion of peripheral pool of putative T(reg) cells in IBD patients and with few effects in controls.
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PMID:Anti-inflammatory effects of probiotic yogurt in inflammatory bowel disease patients. 1759 Jan 76

Tumor necrosis factor (TNF) plays an important part in the pathogenesis of several inflammatory diseases. Its expression is highly increased in inflamed mucosa of inflammatory bowel disease, and anti-TNF treatment appears to improve mucosal inflammation in these patients. However, the role of TNF in the pathogenesis remains to be investigated. In the present study, an experimental colitis was induced by transfer of syngeneic CD45RB(high)CD4(+) T cells into SCID mice. Quantitative analysis of interleukin (IL)-23p19 and IL-17 mRNA was demonstrated to be markedly increased in inflamed colon 4 and 8 weeks after CD45RB(high)CD4(+) T-cell transfer. These SCID recipients were treated i.p. with anti-TNF mAb starting at the beginning (early treatment) or 4 weeks (delayed treatment) after T-cell transfer to investigate the in vivo relevance of TNF to the pathogenesis. The results demonstrated that early treatment with anti-TNF effectively prevented intestinal mucosal inflammation, as evidenced by gradual increase of body weight and absence of diarrhea. Anti-TNF significantly suppressed leukocyte infiltration in the inflamed colon, and down-regulated IFN-gamma, IL-2 and TNF secretion by lamina propria CD4(+) T cells. Interestingly, anti-TNF also significantly decreased expression of IL-23p19 and IL-17 in inflamed colon. Moreover, delayed anti-TNF treatment demonstrated to markedly improve mucosal inflammation. The data suggest that administration of anti-TNF reverses mucosal inflammation via down-regulated pro-inflammatory cytokines, particularly IL-23p19 and IL-17, and decreased leukocyte infiltration in the bowel, thus providing additional relevance of target therapy against TNF.
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PMID:Blockage of tumor necrosis factor prevents intestinal mucosal inflammation through down-regulation of interleukin-23 secretion. 1780 96


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