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)

Although genetic predisposition for inflammatory bowel disease (IBD) is well established, little is known about the accountable genes. The pathogenesis of IBD is characterized by an imbalanced activation of Th1- and Th2-lymphocytes. IL-10 represents an anti-inflammatory cytokine which downregulates the production of Th1-derived cytokines. To evaluate the role of the IL-10 gene in IBD, two polymorphisms in the promoter region (G/A at position -1082 and C/A at position -592) were genotyped in 142 patients with Crohn's disease (CD), 104 patients with ulcerative colitis (UC), and 400 healthy controls. Significant differences were not apparent, neither in the allele frequencies of either polymorphism, nor in the haplotype frequencies. Screening of the coding region of the IL-10 gene by polymerase chain reaction--single strand conformation polymorphism (PCR-SSCP) analysis revealed a rare sequence variation in exon 1 leading to an amino acid exchange (G-->A; G15R) in two patients with CD and five healthy controls. Therefore, polymorphisms of the IL-10 gene are not demonstrably involved in the predisposition of IBD in our cohorts of patients.
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PMID:The IL-10 gene is not involved in the predisposition to inflammatory bowel disease. 1127 74

Spondyloarthropathies (SpA) are a group of related disorders. The hallmark symptoms include spondylitis, pauci-articular synovitis and enthesiopathy. In an important number of cases, subclinical gut inflammation with pathological findings resembling Crohn's disease can be found. Some of these patients may eventually develop overt Crohn's disease. Conventional medical therapy in patients with SpA consists of non-steroidal anti-inflammatory drugs (NSAIDs). Sulphasalazin can be co-administered, especially in cases of chronic synovitis or enthesiopathy. Recently, experience with anti-TNF-alpha monoclonal antibodies (infliximab), a new class of biological compounds, has opened new avenues for treating patients with SpA. In particular, infliximab used in two open studies gave significant benefit on the locomotor manifestations in patients with Crohn's disease, in patients with ankylosing spondylitis, undifferentiated SpA and psoriatic arthritis. Etanercept, another TNF-alpha antagonist (soluble receptor), was shown to induce benefit in a placebo-controlled study in patients with psoriatic arthritis. The relationship between SpA and inflammatory bowel disease lead to the hypothesis that interfering with gut inflammation in patients with SpA would yield a potential target for modulating the synovitis in these patients. Thus, besides TNF-alpha blockade, other strategies with potential efficacy can be envisioned, such as IL-10, ICAM-1 antisense or anti-(4)beta(7) antibodies.
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PMID:Current use of biologicals for the treatment of spondyloarthropathies. 1133 71

IL-10-deficient (IL-10(-/-)) mice develop colitis with many similarities to Crohn's disease. Daily IL-10 injections have a short systemic half-life and are unable to induce complete remission in IL-10(-/-) mice with established disease. In this paper, we investigate the duration, potency, and immunogenicity of gene therapy using an adenoviral vector encoding murine IL-10 (AdvmuIL-10). A single systemic injection of AdvmuIL-10 was sufficient not only to prevent the onset of colitis for at least 10 wk but also to induce clinical and histological remission in mice with established disease. In addition, AdvmuIL-10 diminished the systemic manifestations of disease, including elevated acute-phase proteins, as well as the local consequences of inflammation such as raised stool IL-1beta concentrations. Both IL-10 protein and the effects of secreted IL-10 were detectable for 10 wk after AdvmuIL-10 injection. Furthermore, the immunoregulatory effect of a single AdvmuIL-10 injection was manifest both by a reduction in TNF-alpha, IFN-gamma, and RANTES release from stimulated splenocyte cultures, and also by a change in the proportion of CD45RB(high/low) lymphocytes in the spleen compared with control mice. The delivery of AdvmuIL-10 resulted in a significantly diminished host antiadenoviral response compared with control adenoviral vectors. Thus, gene therapy strategies using adenoviral vectors encoding immunoregulatory and antiinflammatory cytokines may prove to be a potent approach for the treatment of chronic inflammatory disease. Antiinflammatory cytokine expression protects against immune responses directed at gene vectors.
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PMID:The prevention and treatment of murine colitis using gene therapy with adenoviral vectors encoding IL-10. 1139 May 20

An aberrant T cell response to enteric bacteria is important in inflammatory bowel disease. However, the identity of relevant microbial antigens is unknown. Here, we report the presence of I2, a Crohn's disease-associated microbial gene, in the murine intestine. The I2 protein induced a proliferative and IL-10 response by CD4(+) T cells from unimmunized mice. The I2 response was dependent on MHC class II-mediated recognition but did not require antigen processing. Selective activation was observed for the TCR-Vbeta5 subpopulation. These findings indicate that the I2 protein is a new class of T cell superantigen and suggest that colonization by the I2 microorganism in susceptible hosts may provide a superantigenic stimulus pertinent to Crohn's disease pathogenesis.
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PMID:The Crohn's disease-associated bacterial protein I2 is a novel enteric t cell superantigen. 1148 46

T lymphocytes and their cytokines have an important role in the regulation of immune responses in the gut and in the pathogenesis of intestinal inflammation such as in Crohn's disease. The aim of this study was to analyse the Th1/Th2 cytokine profile (IFN-gamma, IL-2, IL-4 and IL-10) in intraepithelial lymphocytes (IEL) and lamina propria lymphocytes (LPL) in Crohn's disease (CD) and ulcerative colitis (UC) in relation to healthy controls (C). Colonic and ileal biopsy specimens were obtained from controls (n = 13) and patients with CD (n = 32). Colonic biopsies were obtained from patients with UC (n = 11). Intracytoplasmic IFN-gamma, IL-2, IL-4 and IL-10 were determined by flow cytometry after PMA-ionomycin stimulation in IEL and LPL. In colonic LPL, a significant proportional decrease of IFN-gamma and IL-2 producing CD3+ cells was observed in patients with CD and UC compared to controls. In ileal LPL, a similar tendency was found although differences were not significant. In IEL no differences in cytokine profiles could be observed. Flow cytometric analysis of intracytoplasmic cytokines at single cell level showed a proportional decrease of IFN-gamma and IL-2 producing T cells in colonic lamina propria in patients with inflammatory bowel disease.
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PMID:The proportion of Th1 cells, which prevail in gut mucosa, is decreased in inflammatory bowel syndrome. 1153 45

In Crohn's disease, intestinal lamina propria (LP) T cells overproduce TNF-alpha and IFN-gamma, and clinical and animal studies indicate that this is pathogenic. Thalidomide influences cytokine production by leukocytes, inhibiting macrophage TNF-alpha, and is beneficial in treating Crohn's disease. Chemical analogues have been synthesized that may lack teratogenic and other side effects of thalidomide. We tested three analogues [selective cytokine inhibitory drugs (SelCIDs) A, B, and C, all potent PDE4 inhibitors] for effect on TNF-alpha, IFN-gamma, and IL-10 production by and on proliferation of intestinal LP mononuclear cells after T-cell stimulation and results were compared with those for peripheral blood leukocytes (PBL). While thalidomide itself had little effect, the SelCIDs were potent inhibitors, with relative inhibitory potencies: A> or =B>>C. The LP T cells were less sensitive to inhibition by the SelCIDs than were PBL. Since highly pre-activated PBL were even less sensitive, activation state alone can account for the responsiveness of intestinal LP T cells. Thalidomide analogues could play a role in treating Crohn's disease and other inflammatory disorders.
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PMID:Potent inhibition of cytokine production from intestinal lamina propria T cells by phosphodiesterase-4 inhibitory thalidomide analogues. 1172 8

Neutralization of TNF-alpha in humans with rheumatoid arthritis or Crohn's disease has been associated with the development of humoral autoimmunity. To determine the effect of TNF-alpha neutralization on cell-mediated and humoral-mediated responses, we administered anti-TNF-alpha mAb to mice undergoing acute graft-vs-host disease (GVHD) using the parent-into-F(1) model. In vivo neutralization of TNF-alpha blocked the lymphocytopenic features characteristic of acute GVHD and induced a lupus-like chronic GVHD phenotype (lymphoproliferation and autoantibody production). These effects resulted from complete inhibition of detectable antihost CTL activity and required the presence of anti-TNF-alpha mAb for the first 4 days after parental cell transfer, indicating that TNF-alpha plays a critical role in the induction of CTL. Moreover, an in vivo blockade of TNF-alpha preferentially inhibited the production of IFN-gamma and blocked IFN-gamma-dependent up-regulation of Fas; however, cytokines such as IL-10, IL-6, or IL-4 were not inhibited. These results suggest that a therapeutic TNF-alpha blockade may promote humoral autoimmunity by selectively inhibiting the induction of a CTL response that would normally suppress autoreactive B cells.
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PMID:In vivo neutralization of TNF-alpha promotes humoral autoimmunity by preventing the induction of CTL. 1173 98

We investigated whether a lack of IL-10 production or responsiveness could be involved in Crohn's disease pathogenesis. Lamina propria mononuclear cells, isolated from the ilea of Crohn's disease patients (n = 16) and controls (n = 13), were activated with anti-CD3 mAb in the presence of CD80 transfectants or LPS +/- IFN-gamma. No evidence for deficient IL-10 production by either T cells or macrophages in Crohn's disease was found. However, the efficacy of rhIL-10 to down-regulate IFN-gamma and especially TNF production in cell cultures from the involved tissues of Crohn's disease patients was poor, and the use of an anti-IL-10R mAb even provided evidence for proinflammatory effects of IL-10. This lack of IL-10 effect possibly results from IL-12 activity. We conclude that IL-10 exhibits poor anti- and even potential proinflammatory effects on ileal Crohn's disease lamina propria. These data might explain the lack of therapeutic efficacy when IL-10 is given to Crohn's disease patients.
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PMID:Decreased lamina propria effector cell responsiveness to interleukin-10 in ileal Crohn's disease. 1178 Oct 69

Current therapy of inflammatory bowel disease, ie, ulcerative colitis and Crohn's disease, is neither sufficient nor disease-modifying. Long-term treatment with non-specific antiinflammatory drugs aminosalicylates, corticosteroids and immunosuppressants is often accompanied with undesirable and potentially serious side effects. Novel biologically-driven therapies are targeted to specific pathophysiological processes, offering the potential for better treatment outcomes. Among other antiinflammatory peptides and proteins, monoclonal antibodies directed against TNFalpha and adhesion molecule alpha4beta7 integrin, recombinant anti-inflammatory cytokines IL-10 and IL-11, as well as colony-stimulating factors and peptide growth factors, are in the most advanced stages of clinical development for IBD.
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PMID:Anti-inflammatory peptides and proteins in inflammatory bowel disease. 1189 Mar 53

IL-10 is an important regulatory cytokine in the mucosal immune system, as supported by the fact that mice deficient in IL-10 spontaneously develop Crohn's disease-like colitis. An aberrant, Th1-driven CD4(+) T-cell response to enteric bacteria seems to be important in the pathogenesis of this murine colitis. However, no specific bacteria or bacterial products have been identified, and whether the colitis is mediated by the activation of CD4(+) T cells that recognize specific peptide-MHC complexes is controversial. In this study, we analyzed the TCR beta chain complementarity determining region 3 length spectratype of colonic CD4(+) T cells isolated from diseased IL-10-deficient mice by using the Immunoscope technique. Screening of the diseased interleukin-10-deficient mice resulted in a restricted clonotype in TCR V beta 13 and 14 subfamilies of colonic CD4(+) T cells. In contrast, a Gaussian distribution of clonotype of individual TCR V beta subsets was observed in CD4(+) T cells from the peripheral lymphoid tissues. Although individual variability in the disease-related response was also noted in other IL-10-deficient mice maintained in La Jolla and Osaka, perhaps because of different stages of the disease, genetic background, or the housing environment, colitis-related public clones seemed to be shared in all the diseased mice tested. To address whether public clones were involved, we determined the DNA sequence of the clones. Public motifs were shared in colonic CD4(+) T cells from different background interleukin-10-deficient mice with colitis. The frequently found motifs were SXDWG and SATGNYAEQ. These motifs were not seen in the peripheral lymphoid tissues of diseased mice as well as the colon of non-diseased mice. Thus, the common motif may be related to a public gut-derived antigen, which could be important for the development of pathogenic CD4(+) T cells in this inflammatory bowel disease (IBD) model. The selection of V beta-J beta usage is perhaps stochastic in individual mice; however, the epigenetic generation of SXDWG motif by the recombination machinery and selection for this motif in the gut environment could be important for triggering IBD.
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PMID:Colitis-related public T cells are selected in the colonic lamina propria of IL-10-deficient mice. 1189 Jul 10


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