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

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 rapid rise in prevalence of ulcerative colitis (UC) and Crohn's disease (CD) in highly developed countries suggests that environmental change engenders risk for inflammatory bowel disease (IBD). Eradication of parasitic worms (helminths) through increased hygiene may be one such change that has led to increased prevalence of these diseases. Helminths alter host mucosal and systemic immunity, inhibiting dysregulated inflammatory responses. Animals exposed to helminths are protected from experimental colitis, encephalitis, and diabetes. Patients with CD or UC improve when exposed to whipworm. Lamina propria (LP) mononuclear cells from helminth-colonized mice make less interleukin (IL)-12 p40 and IFN-gamma, but more IL-4, IL-13, IL-10, TGF-beta, and PGE(2) compared to LP mononuclear cells from naive mice. Systemic immune responses show similar skewing toward Th2 and regulatory cytokine production in worm-colonized animal models and humans. Recent reports suggest that helminths induce regulatory T cell activity. These effects by once ubiquitous organisms may have protected individuals from many of the emerging immune-mediated illnesses like IBD, multiple sclerosis, type I diabetes, and asthma.
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PMID:Role of helminths in regulating mucosal inflammation. 1595 81

Crohn's disease (CD) is a chronic inflammatory pathology of the intestine, characterized by diarrhea and weight loss. A healing effect of vasoactive intestinal peptide (VIP) in the murine model of CD based on 2,4,6-trinitrobencene sulfonic acid (TNBS) administration has been previously shown. The aim of this work was to analyze the expression of several mediators related to the inflammatory cascade in colitic and VIP-treated animals. With this aim, mice received either only TNBS or TNBS and VIP treatment on alternate days. cDNA microarray analysis and real-time polymerase chain reaction were performed on total mRNA from colon to study the expression of a battery of proinflammatory molecules such as the enzyme COX-2, the chemokines CX3CL1, CXCL12, CXCL13, CXCL14, CCR5, and CXCR2, and the cytokines interleukin (IL)-1beta, IL-12, IL-18, IL-10, interferon-gamma, and IL-4. TNBS administration induced the expression of all the proinflammatory mediators studied, whereas VIP treatment reduced their levels, increasing the anti-inflammatory IL-10 and the TH2 cytokine IL-4, explaining its beneficial action through inhibition of the inflammatory/TH1 response. These data describe not only the relation of several proinflammatory mediators to the development of TNBS colitis, reporting their time-course, but also show the beneficial action of VIP in this model through complete blockage of the inflammatory cascade and recovery of the colon homeostasis, providing a potential new alternative for CD therapy.
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PMID:cDNA array analysis of cytokines, chemokines, and receptors involved in the development of TNBS-induced colitis: homeostatic role of VIP. 1597 23

NOD1 is an intracellular pattern-recognition receptor specific for Gram-negative peptidoglycan that is important in host response to infections (e.g. Helicobacter pylori and Shigella flexneri). Genetic variation in NOD1 predisposes to asthma and inflammatory bowel disease. Functional responses have not previously been studied in primary human cells. NOD1 activation by low nanomolar concentrations of the specific muropeptide ligand M-TriDAP induced minimal human peripheral blood mononuclear cell TNF-alpha, IL-1beta or IL-10 secretion, but synergistically increased Toll-like receptor (TLR)-induced responses. Synergistic responses were seen across multiple ligands (to TLR1/2, 2/6, 4, 5, 7/8) and a broad range of cytokine secretion (TNF-alpha, IL-1alpha, IL-1beta, IL-4, IL-6, IL-10, GM-CSF). Synergy was also observed in the allogeneic mixed lymphocyte reaction. These responses were similar in cells homozygous for Crohn's disease-associated NOD2 mutations. In contrast to cell lines, primary human peripheral blood mononuclear cells respond to NOD1 muropeptides at approximately 100-fold lower concentrations. Cross-talk between cytosolic NOD1 and membrane-bound TLR enhances responses to the multiple antigens simultaneously presented by a microbe.
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PMID:Synergistic enhancement of Toll-like receptor responses by NOD1 activation. 1602 3

4-1BB (CDw 137), a member of the tumor necrosis factor receptor (TNFR) superfamily, is a costimulatory receptor primarily expressed on activated T cells. It has been shown that the administration of agonistic anti-4-1BB monoclonal antibody (mAb) enhances tumor immunity and allogenic immune responses. Paradoxically, we found that the administration of anti-4-1BB mAb reduced the incidence and severity of inflammatory bowel disease. In this study, we investigated the effects of anti-4-1BB mAb in a murine intestinal inflammation model, which induced by the hapten reagent, 2,4,6-trinitrobenzene sulfonic acid (TNBS) and mimics immunologic characteristics of human Crohn's disease (CD). Colitis was induced by rectal administration of 2mg of TNBS in 35% ethanol using a vinyl catheter positioned 4cm from the anus. All mice were sacrificed 3 and 10 days after the TNBS administration. The disease activity index (DAI), histological changes of the colon and production of cytokines (IL-2, IL-4, IL-10 and IFN-gamma) were evaluated. The surface molecules of T cells in peripheral blood, spleen and mesenteric lymph nodes were analyzed by flow cytometry. When mice were treated with anti-4-1BB mAb, improvement in both wasting and histopathologic signs of colonic inflammation was observed. The increase a number of splenic CD4(+)CD25(+) T cells and decreased synthesis of the Th1 cytokine IL-2 also occurred. Interestingly, increased production of Th1 cytokine IFN-gamma and proportion of CD8(+) T cells were observed in mice treated with anti-4-1BB mAb in comparison to the colitic mice. These studies show, for the first time, that agonistic anti-4-1BB mAb can improve experimental colitis by reduction of IL-2 and augmentation of CD4(+)CD25(+) regulatory T cells. TNBS colitis is Th1-mediated and has similar histologic features and distribution of inflammation to CD. This study suggests that anti-4-1BB mAb therapy could be effective in the treatment of patients with CD.
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PMID:Administration of agonistic anti-4-1BB monoclonal antibody leads to the amelioration of inflammatory bowel disease. 1602 55

In the inflammatory bowel diseases (IBD) that affect dogs and cats there appears to be dysregulation of normal mucosal immunity, characterised by polyclonal lymphocytic infiltrates which are presumably specific for luminal antigens. There is an absence of a classical polarisation of either T-helper (Th) 1 or Th2 cytokine responses, although increased expression of mRNA for interleukin (IL) 2 and IL-12p40 and a shift towards mucosal immunoglobulin (Ig) G production are consistent findings, whilst variable responses are seen in tumour necrosis factor-alpha (TNF-alpha), IL-1, IL-4, IL-6, and interferon-gamma (IFN-gamma). Increased mucosal permeability and deranged intestinal motility are common sequelae. Despite obvious similarities with Crohn's disease and ulcerative colitis in humans, important differences exist. Of these, the diffuse superficial nature but with no Th1 or Th2 bias, and the prevalence of proximal small intestinal disease are notable. Potential hypotheses for these disparities include specific differences in the types or locations of agonistic gut flora, diffuse abnormalities in microbial-host interactions, a greater importance of diet, or anatomical or cellular differences in mucosal immune responses. Although specific pathogens and genetic susceptibilities may be involved, quantitative or qualitative changes in the normal flora or abnormal responses to a normal flora are more likely to be involved in the immunopathogenesis. Dietary influences include a large source of antigen, promotion of abnormal microbial growth through Maillard compounds within canned diets, and specific macro- and micronutrient deficiencies. Although dependent on a histopathological diagnosis, limitations of biopsies procured endoscopically, lack of histopathological standardisation and difficulty distinguishing inflammation from neoplasia remain significant problems. Clinician-pathologist dialogue, immunohistochemistry, cytokine profiling and lymphocyte clonality assessment may lead to more accurate diagnoses, a deeper understanding of the immunopathogenesis, and ultimately to new therapies or prevention of disease induction.
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PMID:Chronic inflammatory disorders of the gastrointestinal tract of companion animals. 1603 40

Summary CD4(+)CD25(+) regulatory T cells (T(regs)) are involved in the maintenance of peripheral tolerance and ensure a balanced immune response competent of fighting pathogens and at the same time recognizing commensals as harmless. This feature is lost in Crohn's disease (CD). The forkhead/winged helix transcription factor FoxP3 is a master gene for T(reg) function and defects in the FoxP3 gene lead to a clinical picture similar to inflammatory bowel disease (IBD). Murine colitis can be cured by adoptive transfer of T(regs) and ex vivo-generated gut-specific T(regs) represent an attractive option for therapy in CD. Thus, defective T(regs) could contribute to the development of CD. We cultured biopsies of colonic mucosa in the presence of high concentrations of interleukin (IL)-2 and IL-4 to overcome the anergic nature of naturally occurring CD4(+)CD25(+) T(regs) in the mucosa. We investigated the expression of FoxP3 and regulatory potential of gut-derived CD4(+)CD25(+) T cells cultured from patients with CD and healthy individuals. The FoxP3 expression was analysed by reverse transcriptase polymerase chain reaction (RT-PCR), and the suppressive effect of FoxP3(+)CD4(+)CD25(+) T cells on proliferation and cytokine production of autologous CD4(+) T cells was assessed by flow cytometry. Cultured gut-derived T cells with CD4(+)CD25(+) phenotype expressed FoxP3 and were able as the freshly isolated T(regs) from peripheral blood to suppress proliferation and cytokine production of autologous CD4(+) T cells. Thus, we demonstrate that FoxP3(+)CD4(+)CD25(+) T cells with regulatory properties can be propagated in vitro from inflamed mucosa of CD patients, which may be of interest in adoptive immunotherapy.
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PMID:FoxP3(+)CD4(+)CD25(+) T cells with regulatory properties can be cultured from colonic mucosa of patients with Crohn's disease. 1604 46

Despite all of the advances in our understanding of the pathophysiology of inflammatory bowel disease (IBD), we still do not know its cause. Some of the most recently available data are discussed in this review; however, this field is changing rapidly and it is increasingly becoming accepted that immunogenetics play an important role in the predisposition, modulation and perpetuation of IBD. The role of intestinal milieu, and enteric flora in particular, appears to be of greater significance than previously thought. This complex interplay of genetic, microbial and environmental factors culminates in a sustained activation of the mucosal immune and non-immune response, probably facilitated by defects in the intestinal epithelial barrier and mucosal immune system, resulting in active inflammation and tissue destruction. Under normal situations, the intestinal mucosa is in a state of 'controlled' inflammation regulated by a delicate balance of proinflammatory (tumour necrosis factor [TNF]-alpha, interferon [IFN]-gamma, interleukin [IL]-1, IL-6, IL-12) and anti-inflammatory cytokines (IL-4, IL-10, IL-11). The mucosal immune system is the central effector of intestinal inflammation and injury, with cytokines playing a central role in modulating inflammation. Cytokines may, therefore, be a logical target for IBD therapy using specific cytokine inhibitors. Biotechnology agents targeted against TNF, leukocyte adhesion, T-helper cell (T(h))-1 polarisation, T-cell activation or nuclear factor (NF)-kappaB, and other miscellaneous therapies are being evaluated as potential therapies for IBD. In this context, infliximab is currently the only biologic agent approved for the treatment of inflammatory and fistulising Crohn's disease. Other anti-TNF biologic agents have emerged, including CDP 571, certolizumab pegol (CDP 870), etanercept, onercept and adalimumab. However, ongoing research continues to generate new biologic agents targeted at specific pathogenic mechanisms involved in the inflammatory process. Lymphocyte-endothelial interactions mediated by adhesion molecules are important in leukocyte migration and recruitment to sites of inflammation, and selective blockade of these adhesion molecules is a novel and promising strategy to treat Crohn's disease. Therapeutic agents that inhibit leukocyte trafficking include natalizumab, MLN-02 and alicaforsen (ISIS 2302). Other agents being investigated for the treatment of Crohn's disease include inhibitors of T-cell activation, peroxisome proliferator-activated receptors, proinflammatory cytokine receptors and T(h)1 polarisation, and growth hormone and growth factors. Agents being investigated for treatment of ulcerative colitis include many of those mentioned for Crohn's disease. More controlled clinical trials are currently being conducted, exploring the safety and efficacy of old and new biologic agents, and the search certainly will open new and exciting perspectives on the development of therapies for IBD.
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PMID:Biologic therapy for inflammatory bowel disease. 1626 94

The pathogenesis of Crohn's disease has been associated with a dysregulated response of the mucosal immune system against intraluminal Ags of bacterial origin. In this study, we have investigated the effects of germfree (GF) conditions in the SAMP1/YitFc murine model of Crohn's disease-like ileitis. We show that the bacterial flora is not essential for ileitis induction, because GF SAMP1/YitFc mice develop chronic ileitis. However, compared with disease in specific pathogen-free (SPF) mice, ileitis in GF mice is significantly attenuated, and is associated with delayed lymphocytic infiltration and defective mucosal expression of Th2 cytokines. In addition, we demonstrate that stimulation with purified fecal Ags from SPF, but not GF mice leads to the generation of IL-4-secreting effector lymphocytes. This result suggests that commensal bacteria drive Th2 responses characteristic of the chronic phase of SAMP1/YitFc ileitis. Finally, adoptive transfer of CD4-positive cells from GF, but not SPF mice induces severe colitis in SCID recipients. These effects were associated with a decreased frequency of CD4(+)CD25(+)Foxp3(+) T cells in the mesenteric lymph nodes of GF mice compared with SPF mice, as well as lower relative gene expression of Foxp3 in CD4(+)CD25(+) T cells in GF mice. It is therefore apparent that, in the absence of live intraluminal bacteria, the regulatory component of the mucosal immune system is compromised. All together, our results indicate that in SAMP1/YitFc mice, bacterial flora exacerbates intestinal inflammation, but is not essential for the generation of the chronic ileitis that is characteristic of these mice.
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PMID:Commensal bacteria exacerbate intestinal inflammation but are not essential for the development of murine ileitis. 1723 31

The authors review advances about altered immunological cellular mechanisms in inflammatory bowel diseases (IBD). The innate immune response might play a role in the inductive phase : epithelial barrier defect, production of inflammatory cytokines and defective neutrophil function. Dendritic cells have a pivotal role, since they sense the nature of the micro-organisms in the intestine in order to drive either adaptive immune responses through IL-12 or IL-4 and co-stimulatory molecules, or immunotolerance through regulatory T cells (Tr). T helper(Th)1 cytokines (IFNgamma, TNF-alpha, IL-12) are secreted in excess in Crohn's disease (CD) whereas in ulcerative colitis an atypical Th2 immune response (IL-4, TGFbeta) has been reported. However, activation of Th can only lead to effective immune response if co-stimulatory molecules expressed on activated T cells bind to their specific ligands on the antigen-presenting-cells, mesenchymal and endothe-, lial cells. This binding is necessary to generate an effective immune response, to enhance expression of adhesion molecules and T cell recruitment, promoting chronic inflammation in IBD. A defective function of Tr might contribute to excessive T cell response. Innate CD4 + CD25 + Tr derived from the thymus represent 5-10% of T cells in peripheral lymphoid organs. Acquired peripheral Tr downregulate the immune response through IL-10 and TGF-beta production. In IBD effector T cells might downregulate the development of Tr cells in the thymus. Another defective mechanism in CD is T cell resistance to apoptosis, leading to inappropriate immune homeostasis and accumulation of T cells in the tissues. New therapeutic agents have been proposed for correcting deficiencies of innate immunity or reducing excessive immune responses, with promising results confirmed by randomized controlled trials.
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PMID:New insights into the cellular immunology of the intestine in relation to the pathophysiology of inflammatory bowel diseases. 1734 83


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