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

We have described recently that TNBS-induced colitis, an animal model of chronic inflammatory bowel disease (IBD), can be cured by treatment with anti-CD44v7. This finding led us to evaluate whether CD44v7 may be of functional importance in patients with IBD. Expression of CD44 variant isoforms (CD44v) has been evaluated on PBMC of 46 patients with IBD, 43 patients with autoimmune diseases not affecting the gastrointestinal tract, 26 patients with nonautoimmune disease, and 24 healthy donors. In all groups, expression of CD44v on freshly harvested PBMC was not above or was borderline above background levels. After in vitro stimulation, expression of CD44 standard (CD44s) and CD44v6 was strongly up-regulated. Exclusively on PBMC of patients with autoimmune disease, high expression of CD44v3 and CD44v7 was observed. CD44v3 and CD44v7 were mainly expressed on subsets of CD4+ lymphocytes, B cells, and monocytes; CD44v6 was predominantly detected on CD4+ and CD8+ cells. Considering functional activity, CD44v7 apparently exerted a dual effect. After culturing PBMC in the presence of anti-CD44v7, a higher percentage of cells produced IL-10. This was irrespective of whether the PBMC were derived from healthy donors or from patients with autoimmune disease or IBD. On the other hand, PBMC of all donors proliferated upon cross-linking of CD3 and CD44s or CD3 and CD44v6. Instead, costimulatory activity of CD44v7 was seen only in PBMC of patients with autoimmune disease and IBD. Because expression and function of CD44v7 in patients with systemic autoimmune disease and IBD have been much like the ones in mice suffering of TNBS-induced colitis, it is tempting to speculate that blockade of CD44v7 could also be of therapeutic relevance in the human diseases.
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PMID:CD44 variant isoforms on blood leukocytes in chronic inflammatory bowel disease and other systemic autoimmune diseases. 1037 17

To investigate the role of IFN-gamma in the immunopathogenesis of inflammatory bowel disease (IBD), severe combined immunodeficient (SCID) mice were transplanted with in vitro activated CD4+ T cells from either wild-type (WT) or IFN-gamma-deficient (IFN-gammaKO) BALB/c mice. In vitro, the two types of T cells displayed comparable proliferation rates and production of tumour necrosis factor-alpha (TNF-alpha), IL-2, IL-4 and IL-10 after concanavalin A (Con A) stimulation. When transplanted into SCID mice, WT CD4+ blasts induced a lethal IBD, whereas IFN-gammaKO blasts induced a less severe intestinal inflammation with moderate weight loss. Intracellular cytokine staining of lamina propria lymphocytes (LPL) revealed comparable fractions of CD4+ T cells positive for TNF-alpha, IL-2 and IL-10 in the two groups of transplanted SCID mice, whereas a two-to-three-fold increase in the fraction of IL-4-positive cells was found in IFN-gammaKO-transplanted SCID mice. Flow cytometric analyses showed strong up-regulation of MHC class II expression of colonic epithelial cells of WT-CD4+ T cell-transplanted compared with IFN-gammaKO-transplanted SCID mice. A significantly higher fraction of CD4+ LPL were found to enter the cell cycle, i.e. to incorporate bromo-deoxy-uridine, and to undergo apoptosis in vivo in WT-transplanted compared with IFN-gammaKO-transplanted SCID mice. These data point towards an important role for IFN-gamma in the development of IBD in SCID mice. The inflammation might be initiated and subsequently enhanced by the ability of IFN-gamma to induce de novo MHC class II expression in the colonic epithelium, a change which could lead to increased antigen processing and production of local proinflammatory cytokines, CD4+ T cell turnover and thereby to exaggeration of disease.
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PMID:In vitro activated CD4+ T cells from interferon-gamma (IFN-gamma)-deficient mice induce intestinal inflammation in immunodeficient hosts. 1054 Jan 83

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.
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PMID:[Present states of development in new drugs and treatment of inflammatory bowel disease]. 1057 18

The normal intestinal epithelium provides a barrier relatively impermeable to luminal constituents. However, patients with inflammatory bowel disease experience enhanced intestinal permeability that correlates with the degree of injury. IL-10 gene-deficient mice were studied to determine whether increased intestinal permeability occurs as a primary defect before the onset of mucosal inflammation or is secondary to mucosal injury. At 2 weeks of age, IL-10 gene-deficient mice show an increase in ileal and colonic permeability in the absence of any histological injury. This primary permeability defect is associated with increased mucosal secretion of interferon-gamma and tumor necrosis factor-alpha, and does not involve an increase in nitric oxide synthase activity. Colonic permeability remains elevated as inflammation progresses, while ileal permeability normalizes by 6 weeks of age. IL-10 gene-deficient mice raised under germ-free conditions have no inflammation, and demonstrate normal permeability and cytokine levels. This data suggests that the intestinal permeability defect in IL-10 gene-deficient mice occurs due to a dysregulated immune response to normal enteric microflora and, furthermore, this permeability defect exists prior to the development of mucosal inflammation.
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PMID:Interleukin-10 gene-deficient mice develop a primary intestinal permeability defect in response to enteric microflora. 1057 19

Animal models of inflammatory bowel disease (IBD) have been useful in the identification of those immune responses uniquely involved in IBD pathogenesis and in defining the important roles of environmental influences, such as normal luminal bacterial flora and the genetic composition of the host, in modifying IBD-associated inflammation. Recent studies have focused particular attention on CD4+ T cells which produce excessive quantities either of Th1 cytokines (IFN-gamma and TNF) directed by IL-12 or of a Th2 cytokine (IL-4), relative to the production of suppressive cytokines such as IL-10 and transforming growth factor beta. Such insights will be extremely beneficial in the development of novel approaches to the control of IBD-type inflammation, such as the use of anticytokine therapies and gene therapy, and finally, in the identification of the genetic abnormalities and the antigens driving the inflammation that underlies the human disease.
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PMID:Animal models of mucosal inflammation and their relation to human inflammatory bowel disease. 1063 50

Inflammatory bowel diseases (IBD: Crohn's disease, ulcerative colitis) are chronic inflammatory and frequently relapsing diseases of the gut that ultimately lead to destruction of the intestinal tissue. Recent evidence suggests that a pathologic activation of the mucosal immune system in response to antigens is a key factor in the pathogenesis of IBD. Furthermore, changes in cell migration and cytokine production appear to contribute to the perpetuation of IBD and the postoperative recurrence of Crohn's disease. Based on recent advances in our understanding of the pathogenesis of IBD, several new therapeutic strategies are currently being tested in clinical practice, including recombinant anti-inflammatory cytokines (IFN-alpha, IL-10, IL-11) and inhibitors of cell adhesion molecules (ICAM), proinflammatory cytokines (TNF, IL-12) and their receptors (TNF, IL-6R).
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PMID:[Immunopathogenesis of inflammatory bowel diseases]. 1066 99

Cytokines are the key mediators of inflammation in the IBD and are focus of renewed interest to plan therapeutic strategies against this disease. However, there are gaps in our knowledge at present and a lot of questions need clear answers. Even with a therapy as specific as anti-TNF antibody, it is not clear if the benefit is attributable to simple binding and clearance of TNF-alpha or to binding on the cell surface and subsequent deletion of the activated macrophage. When a drug appears to be less effective than pre-clinical models suggest, can failures in effectiveness from delivery or dosing the differentiated? The disappointing results of clinical trials with IL-10 is at odds with the prediction of benefit from animal models. It even brings into question the validity of those models as well as the soundness of design of the clinical trials on which efficacy of IL-10 is assessed. Other exciting new methods to treat IBD could be use of monoclonal antibodies to effector T cell molecules (such as CD4 or CD44v7) removal of such cytokine secreting cells (apheresis), antibodies to proinflammatory cytokines (such as TNF-alpha, IFN-alpha, IFN-gamma, and IL-12) or administration of anti-inflammatory cytokines (such as IL-10, IL-11). Challenges in developing new therapeutic strategies include not only identifying novel agents, but also improving the definitions of clinical endpoints and defining efficacy at the biologic level. There is also need to further refine our knowledge about genetic elements and environment initiators to comprehensively manage IBD.
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PMID:Cytokines and inflammatory bowel disease. 1069 14

German shepherd dogs (GSD) are predisposed to enteropathies such as inflammatory bowel disease (IBD) and small intestinal bacterial overgrowth (SIBO). The present study examined the role of cytokines in the immunopathogenesis of both conditions. Duodenal mucosal biopsies were taken from GSDs with small intestinal enteropathies (group 1; N = 16) or control dogs (group 2, N = 12). IL-2, IL-4, IL-5, IL-10, IL-12p40, IFN-gamma, TNF-alpha, and TGF-beta1 mRNA expression was determined by semiquantitative reverse transcriptase polymerase chain reaction. IL-2, IL-5, IL-12p40, TNF-alpha, and TGF-beta1 mRNA expression in group 1 dogs was significantly greater than in group 2 dogs (all P<0.01), but there were no significant differences between dogs with IBD or SIBO. Further, antibiotic treatment in five dogs with SIBO, resulted in reduced TNF-alpha and TGF-beta1 mRNA expression (P<0.05). Such alterations in cytokine mRNA expression suggest heightened immune responses within the duodenal mucosa in GSDs with either SIBO or IBD.
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PMID:Cytokine mRNA expression in mucosal biopsies from German shepherd dogs with small intestinal enteropathies. 1069 6

Inflammatory bowel diseases are considered to be related to dysregulation of pro- and anti-inflammatory cytokines in the intestinal wall. We investigated the levels of TNFalpha, IFNgamma, and IL-10 mRNA expression in intestinal tissues resected from the patients with Crohn disease (CD) (n=29), ulcerative colitis (UC) (n=8), and controls (n=8) using reverse transcription-polymerase chain reaction (RT-PCR). In addition, we examined the relationship between the expression of these cytokine mRNA and their clinical conditions using CD activity index (CDAI) and Nutritional Surgical Risk Index (NSRI). Compared with controls, tissues in CD showed high levels of TNFalpha and IFNgamma mRNA expression both in inflamed and non-inflamed tissues, and showed high levels of IL-10 mRNA expression in inflamed tissues. In UC, high levels of IL-10 mRNA expression were detected both in inflamed and non-inflamed UC tissues, while those of TNFalpha and IFNgamma were not. In 80% of CD tissues (n=23), levels of IL-10 and TNFalpha expression were interrelated. While the remaining tissues (n=6) showed low levels of IL-10 expression despite high levels of TNFalpha expression in inflamed CD tissues, and 4 of these 6 patients had high CDAI and low NSRI. Furthermore, in low nutritional CD patients (NSRI <40, n=13), the levels of IL-10 mRNA to inhibit pro-inflammatory cytokines were poorer than in good nutritional patients (NSRI >/=40, n=16). These findings suggest the overexpressions of TNFalpha and IFNgamma in CD, and less producibility of IL-10 against these cytokine might lead to development of severe CD.
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PMID:Interleukin-10 expression in intestine of Crohn disease. 1071 56

Inflammatory bowel diseases (IBD) are characterized by a sustained inflammatory cascade that gives rise to the release of mediators capable of degrading and modifying bowel wall structure. Our aims were (i) to measure the production of matrix metalloproteinase-3 (MMP-3), and its tissue inhibitor, tissue inhibitor of metalloproteinase-1 (TIMP-1), by inflamed and uninflamed colonic mucosa in IBD, and (ii) to correlate their production with that of proinflammatory cytokines and the anti-inflammatory cytokine, IL-10. Thirty-eight patients with IBD, including 25 with Crohn's disease and 13 with ulcerative colitis, were included. Ten controls were also studied. Biopsies were taken from inflamed and uninflamed regions and inflammation was graded both macroscopically and histologically. Organ cultures were performed for 18 h. Tumour necrosis factor-alpha (TNF-alpha), IL-6, IL-1beta, IL-10, MMP-3 and TIMP-1 concentrations were measured using specific immunoassays. The production of both MMP-3 and the TIMP-1 were either undetectable or below the sensitivity of our immunoassay in the vast majority of uninflamed samples either from controls or from those with Crohn's disease or ulcerative colitis. In inflamed mucosa, the production of these mediators increased significantly both in Crohn's disease (P < 0.01 and 0.001, respectively) and ulcerative colitis (P < 0.001 and 0.001, respectively). Mediator production in both cases was significantly correlated with the production of proinflammatory cytokines and IL-10, as well as with the degree of macroscopic and microscopic inflammation. Inflamed mucosa of both Crohn's disease and ulcerative colitis show increased production of both MMP-3 and its tissue inhibitor, which correlates very well with production of IL-1beta, IL-6, TNF-alpha and IL-10.
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PMID:Increased production of matrix metalloproteinase-3 and tissue inhibitor of metalloproteinase-1 by inflamed mucosa in inflammatory bowel disease. 1079 71


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