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)

Chronic Schistosoma mansoni infection leads to a type 2-immune response with increased production of interleukin (IL-10). Evidence indicates chronic exposure to S. mansoni down regulates the type 1 immune response and prevents the onset of Th1-mediated diseases such as multiple sclerosis, diabetes mellitus and Crohn's disease. Furthermore, our own studies have revealed that chronic exposure to S. mansoni also down regulates atopic disease, Th2-mediated diseases. Our studies show an inverse association between the skin prick test reactivity and infection with S. mansoni and show the severity of asthma is reduced in subjects living in an endemic area of S. mansoni. Moreover, we hypothesize the mechanisms involved in the modulation of inflammatory response in atopic individuals, is likely dependent on IL-10 production, an anti-inflammatory cytokine elevated during helminth infections. Patients with asthma and helminth infections produced less IL-5 than patients with asthma without helminth infections, and this down regulation could, in part, be mediated by IL-10. In conclusion, helminthic infections, through induction of regulatory mechanisms, such as IL-10 production, are able to modulate the inflammatory immune response involved in the pathology of auto-immune and allergic disease.
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PMID:Schistosoma mansoni infection modulates the immune response against allergic and auto-immune diseases. 1548 31

Inflammatory bowel diseases (IBD), namely ulcerative colitis (UC) and Crohn's disease (CD) are chronic disorders which appear to be immunologically related. The basic therapeutic agents used in IBD treatment are 5-aminosalicilates and corticoids. In cases when this treatment is insufficient, immunosuppressive therapy is recommended. During an acute phase of the illness most useful is cyclosporine A and in the maintenance therapy, azathioprine and 6-mercaptopurine. Because of insufficiency of this classic therapy in many cases, the new, more useful and safe methods of IBD treatment are wanted. Permanent researches have been focused on immunological reactions. The most useful appear to be TNFalpha antagonists (oxpentifilline, infliximab, entanercept, onercept and thalidomide), anti alpha-4 integrin antibodies (natalizumab), IL-10, anti-CD4, IL-6, IL-12, IL-18, IFNgamma, IL-2R antibodies and others. The best clinical experiences are connected with CD treatment using infliximab (monoclonal, chimeric anti TNFalpha antibodies). Its position in IBD therapy appears to be established now, whereas the other methods are still experimental. Most of clinical and experimental data indicate that it is possible to cure severe IBD using agents which affect metabolism of the cytokine playing key role in pathogenesis of the illness. The modern immunotherapy will probably play important role in the future IBD treatment.
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PMID:[Immunotherapy of inflammatory bowel diseases]. 1560 45

A lymphocytic enterocolitis has been reported in a cohort of children with autistic spectrum disorder (ASD) and gastrointestinal (GI) symptoms. This study tested the hypothesis that dysregulated intestinal mucosal immunity with enhanced pro-inflammatory cytokine production is present in these ASD children. Comparison was made with developmentally normal children with, and without, mucosal inflammation. Duodenal and colonic biopsies were obtained from 21 ASD children, and 65 developmentally normal paediatric controls, of which 38 had signs of histological inflammation. Detection of CD3+ lymphocyte staining for spontaneous intracellular TNFalpha, IL-2, IL-4, IFNgamma, and IL-10, was performed by multicolor flow cytometry. Duodenal and colonic mucosal CD3+ lymphocyte counts were elevated in ASD children compared with noninflamed controls (p<0.03). In the duodenum, the proportion of lamina propria (LP) and epithelial CD3(+)TNFalpha+ cells in ASD children was significantly greater compared with noninflamed controls (p<0.002) but not coeliac disease controls. In addition, LP and epithelial CD3(+)IL-2+ and CD3(+)IFNgamma+, and epithelial CD3(+)IL-4+ cells were more numerous in ASD children than in noninflamed controls (p<0.04). In contrast, CD3(+)IL-10+ cells were fewer in ASD children than in noninflamed controls (p<0.05). In the colon, LP CD3(+)TNFalpha+ and CD3(+)IFNgamma+ were more frequent in ASD children than in noninflamed controls (p<0.01). In contrast with Crohn's disease and non-Crohn's colitis, LP and epithelial CD3(+)IL-10+ cells were fewer in ASD children than in nondisease controls (p<0.01). There was a significantly greater proportion of CD3(+)TNFalpha+ cells in colonic mucosa in those ASD children who had no dietary exclusion compared with those on a gluten and/or casein free diet (p<0.05). There is a consistent profile of CD3+ lymphocyte cytokines in the small and large intestinal mucosa of these ASD children, involving increased pro-inflammatory and decreased regulatory activities. The data provide further evidence of a diffuse mucosal immunopathology in some ASD children and the potential for benefit of dietary and immunomodulatory therapies.
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PMID:Spontaneous mucosal lymphocyte cytokine profiles in children with autism and gastrointestinal symptoms: mucosal immune activation and reduced counter regulatory interleukin-10. 1562 51

CD4(+) T helper cells are important for the regulation of immune responses in the intestinal mucosa and they exert their effects through the secretion of pro-inflammatory and immunomodulatory cytokines. Human patients with inflammatory bowel diseases (IBD) such as Crohn's disease and ulcerative colitis have alterations in the normal intestinal cytokine profile. These cytokine abnormalities have been shown at both the protein and messenger RNA (mRNA) level. The role that mucosal cytokines play in the pathogenesis of canine IBD has only been investigated using semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR) analysis of gut tissue, as cytokine antisera are not available for this species. Real-time RT-PCR has been recognised to be a more accurate and sensitive method of quantifying mRNA transcripts, so in this study TaqMan real-time RT-PCR assays for the quantification of mRNA encoding IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-18, IFN-gamma, TNF-alpha and TGF-beta in canine intestinal mucosa were developed. The amount of these templates was quantified in normal canine duodenal mucosa (n = 8). IL-18, TGF-beta and TNF-alpha were found to be the most abundant transcripts, with IL-10 and IFN-gamma present at levels approximately 10-fold less. IL-2, IL-4, IL-5, IL-6 and IL-12 were the least abundant templates, with some RNA samples having no detectable mRNA copies. The methods developed in this study will form the basis of further work investigating the expression of mRNA encoding cytokines in mucosa from dogs with chronic enteropathies. In addition, these real-time PCR assays can also be used for the quantification of canine cytokine mRNA in other diseases.
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PMID:Cytokine mRNA quantification in histologically normal canine duodenal mucosa by real-time RT-PCR. 1562 66

Our understanding of the etiology and pathogenesis of IBD has improved extensively over the past years. At the center of the pathogenesis seems to be an excessive pro-inflammatory immune reaction towards normal intestinal flora. The different factors involved in this concept will form the focus of this review. The initial phase of antigen processing and presentation can be influenced by either modulation of the intestinal flora via antibiotics or probiotics or by direct stimulation of macrophages through GM-CSF treatment. Antigen recognition and activation of T-cells can be down-regulated by immunosuppressives such as azathioprine, CsA or methotrexate thus building the basis for current treatment in IBD. The pro-inflammatory character of the immune reaction is defined by the predominance of certain T-cell subpopulations. By targeting cytokines the disbalance of these subpopulation should be reconstituted. Here we will focus first on preliminary clinical as well as experimental data for the pro-inflammatory mediators IL-12 and IL-18 as well as for the anti-inflammatory cytokine IL-10. Second, the clinical data for the TNFalpha antibody that has been proven to be efficacious in Crohn's disease and the associated risks will be discussed. Last, recent clinical and experimental data on targeting cell adhesion as well as intracellular signaling pathways will be presented. In summary, with regard to this review, treatments, which intervene as early as possible in the initiation of the pathological immune reaction and simultaneously have a favorable side-effect profile, must be the focus of future research.
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PMID:Therapeutic approaches in inflammatory bowel disease based on the immunopathogenesis. 1563 10

A number of rodent models for inflammatory bowel disease (IBD) have been developed, but most cannot be used to develop and validate new therapies for IBD. From the models developed, the IL-10 deficient mouse model is the one that results in a disease similar to human IBD; however, in this model, colitis occurs with variable incidence taking 3-4 months to develop. These are serious problems with the model when evaluating a new therapy because of the large-scale experiments required and the difficulty in performing an accurate pharmacological analysis. In this study, the IL-10 deficient mouse model was modified by transferring whole spleen and mesenteric lymph node cells from IL-10 deficient mice to CB-17 SCID mice. In this IL-10 deficient cell transfer model, chronic intestinal inflammation developed in all recipients within 2-3 weeks, which was far earlier than in donor IL-10 deficient mice. The pathological phenotypes were similar to those of IL-10 deficient mice and CD45RBhi T cell-transfer models. In addition, we assessed several agents for inflammatory bowel disease to validate the general utility of this cell transfer model. It is worth noting that TNFR-Ig or prednisolone, which is effective for treatment of patients with severe-fulminant Crohn's disease, markedly attenuated pathological clinical indices in this colitis model, whereas the immunosuppressive agents, azathioprine, tacrolimus, and cyclosporine A produced no significant effect. These results suggest that the IL-10 deficient cell transfer model is a good experimental model to use for developing new and effective therapies for active IBD.
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PMID:Development and validation of a novel IL-10 deficient cell transfer model for colitis. 1582 15

Recently, the alteration of peripheral T cells has become a focus of attention in research on Crohn's disease (CD). To examine the characteristics of peripheral T cells in CD patients, we analyzed the expression of a memory T cell marker (CD45RO(Bright)CD3+) and the cytokine production by peripheral helper and cytotoxic T cells in patients with CD. With the use of monensin to prevent the secretion of cytokines under stimulation, we measured the count of intracellular cytokine-positive cells for production of interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, interleukin (IL)-2, IL-4, IL-6, IL-10, and granulocyte-macrophage colony stimulating factor (GM-CSF) in the peripheral T cell population using flow-cytometry. The counts of lymphocytes, T cells, and helper T cells in patients with CD were significantly lower than in normal volunteers. Although no difference in the counts of lymphocytes, total T cells, helper and cytotoxic T cells was observed, the counts of intracellular cytokine producing helper T cells in IFN-gamma, TNF-alpha or GM-CSF were significantly higher in active cases than in quiescent cases. These results suggest that stable CD patients are immunosuppressive, and activation of some kinds of T-cells, especially Th1-associated cytokine producing T-cells, correlate with disease progression. Th1-associated cytokine analysis of peripheral T cells may be one of the useful markers to evaluate the activeness of Crohn's disease.
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PMID:Intracellular cytokine patterns of peripheral blood T cells as a useful indicator of activeness of Crohn's disease. 1584 59

The recognition of peptidoglycan by cells of the innate immune system has been controversial; both TLR2 and nucleotide-binding oligomerization domain-2 (NOD2) have been implicated in this process. In the present study we demonstrate that although NOD2 is required for recognition of peptidoglycan, this leads to strong synergistic effects on TLR2-mediated production of both pro- and anti-inflammatory cytokines. Defective IL-10 production in patients with Crohn's disease bearing loss of function mutations of NOD2 may lead to overwhelming inflammation due to a subsequent Th1 bias. In addition to the potentiation of TLR2 effects, NOD2 is a modulator of signals transmitted through TLR4 and TLR3, but not through TLR5, TLR9, or TLR7. Thus, interaction between NOD2 and specific TLR pathways may represent an important modulatory mechanism of innate immune responses.
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PMID:Nucleotide-binding oligomerization domain-2 modulates specific TLR pathways for the induction of cytokine release. 1587 55

Tumor necrosis factor (TNF) antagonism with monoclonal antibodies is an effective therapy for severe Crohn's disease and rheumatoid arthritis. Recent studies have suggested that induction of apoptosis of inflammatory cells contributes to this therapeutic effect. We investigated whether infliximab (a mouse-human IgG1 chimeric anti-TNF monoclonal antibody) could induce apoptosis in vivo in human-mouse chimeras, created by reconstitution of severe combined immunodeficiency/beige mice with THP-1 (human monocytic cell line) or Jurkat cells (human T cell line). Infliximab treatment of chimeric mice depleted spleen and peritoneum from THP-1 cells and Jurkat cells and decreased production of the human cytokines IL-10 and IL-12 in vivo. Cell death was shown to occur already within 1 h of treatment. Infliximab effects were independent of FcgammaR binding or complement activation. Cell death resulted from apoptosis induction in a caspase-dependent pathway, as evidenced by the in vitro protective effect of the pan-caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyketone (Z-VAD-FMK). These data provide support for caspase-dependent apoptosis induction being the mechanism of action of infliximab in vivo.
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PMID:Infliximab induces apoptosis of monocytes and T lymphocytes in a human-mouse chimeric model. 1589 92

Suppression of chronic intestinal inflammation by different subtypes of T cells has been described in recent years. In particular, naturally arising CD4(+)CD25(+) regulatory T cells and IL-10-producing regulatory T cell type 1 CD4(+) T lymphocytes have been implicated in the regulation of intestinal inflammation. Here we focus on the ability of CD4(+)CD25(+) regulatory T cells to suppress innate and T-cell responses and discuss implications for immunoregulation in human inflammatory bowel disease. Besides the modulation of lymphoproliferation, a role for CD4(+)CD25(+) T cells in down-modulation of innate immune responses is emerging and the immunoregulatory activities of regulatory T cells in vivo may be mediated via effects on dendritic cells. Considering the extraordinary regenerative potential of the intestinal mucosa, the ability to impede pathogenic T-cell responses by active regulation might be of particular therapeutic benefit for the treatment of chronic intestinal inflammatory diseases such as Crohn's disease and ulcerative colitis.
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PMID:The role of mucosal T lymphocytes in regulating intestinal inflammation. 1595 82


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