UMLS:C0009319 - FACTA Search

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Query: UMLS:C0009319 (colitis)
19,384 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

T cell activation, differentiation and effector functions depend on signals delivered through the antigen-specific TCR and non-clonal costimulatory receptors on the T cell. Activated T cells express the inducible costimulator (ICOS). We examined the co-expression of ICOS with Th cytokines in mucosal immune responses. ICOS+CD4+ Th cells expressed strikingly different cytokines depending on the type of infection encountered and the cells' anatomical localization. In the Th2-dominated response to Schistosoma mansoni, ICOS expression of CD4+ cells isolated from the liver was strongly associated with the expression of IL-5, IL-10, IL-13, and T1/ST2, but not with the chemokine receptor CXCR5, a pattern consistent with Th2 effector cells. In the secondary lymphatic organs of schistosome-infected mice, ICOS expression was randomly correlated with Th2 effector-cytokines, but positively correlated with CXCR5 expression; a pattern consistent with follicular Th cells. In Th cells isolated from gut or liver of mice infected with Toxoplasma gondii, ICOS expression was positively correlated with IFN-gamma production. Finally, in the severe combined immunodeficiency transfer colitis model, ICOS expression was strongly positively associated with IFN-gamma and IL-2. Thus, ICOS appears to costimulate distinct effector functions in different immune responses, depending on factors such as the nature of the antigen encountered and localization and chronicity of the immune response.
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PMID:ICOS+ Th cells produce distinct cytokines in different mucosal immune responses. 1264 36

CD11c(+) (F4/80(-) CD68(-)) dendritic cells (DC) in the colonic lamina propria (cLP) of normal and immunodeficient (RAG1(-/-)) C57BL/6 (B6) mice show high surface expression of MHC class I/II molecules and CD1d, and low surface expression of CD40, CD80, CD86 costimulator molecules. CD4(+) alpha beta T cells from normal or MHC class II-deficient B6 mice transferred into congenic RAG1(-/-) hosts induce a progressive, lethal colitis. Concomitant with colitis development, DC in the inflamed cLP increase in number and up-regulate surface expression of CD1d, MHC class II molecules and CD40, CD80, CD86 costimulator molecules. cLP DC from non-transplanted (healthy) and transplanted (diseased) mice produce similar amounts of IL-12 p70 and IL-10 in response to CD40 signaling, but the inducible IL-12 p40 release is 5-15-fold higher in mice with colitis than in non-transplanted mice. Binding of IL-12 p40 to p19 generates IL-23. Freshly isolated cLP lymphocytes (cLPL) from transplanted, diseased mice express 3-10-fold more p19 transcripts than cLPL from non-transplanted, healthy mice. p19 expression by cLPL is further up-regulated in response to CD40 ligation. Freshly isolated cLP DC from transplanted mice with colitis (but not from non-transplanted controls) stimulate IFN-gamma (but not IL-4 or IL-13) release by co-cultured NKT cells. Incolitis, DC accumulate in the cLP, show an activated surface phenotype, up-regulate IL-12 p40 and p19 expression, and 'spontaneously' stimulate NKT-like cells. cLP DC may be interesting targets for novel therapeutic approaches to modulate mucosal T cell responses in situ.
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PMID:Colonic lamina propria dendritic cells in mice with CD4+ T cell-induced colitis. 1267 74

Several studies have indicated that active monocytes, such as macrophages and T cells, play an important role in the pathogenesis of chronic human inflammatory bowel disease (IBD), although the etiology remains unclear. Manipulation of these cells appears essential for the treatment of patients with IBD. Recently, considerable attention has been paid to the use of polymer microspheres for the sustained release of various drugs and the targeting of therapeutic agents to their site of action. It was reported that biodegradable poly-D,L-lactic acid (PDLLA) microspheres can be efficiently taken up by macrophages and M cells. We evaluated the effect of a new drug delivery system targeting microfold cells and macrophages with PDLLA microspheres and gelatin microspheres (GM) on colitis models. In the first experiment, colitis was induced in Balb/c mice by 5% dextran sodium sulfate, and microspheres containing dexamethsone (Decadrone, Dx; Dx microspheres) were orally administered to these mice. Serum levels of Dx did not reach a detectable level after administration of Dx microspheres. The tissue distribution of microspheres containing 125I-Dx in inflamed colon was significantly higher than that in other organs. The histological score, myeloperoxidase activity, and nitric oxide production of mice treated with Dx microspheres were significantly lower than in those treated with Dx alone. Gene expression of proinflammatory cytokines was remarkably downregulated in mice treated with Dx microspheres compared to Dx alone. Next, we investigated the effect of elimination of resident macrophages using microspheres containing dichloromethylene diphosphonate (DMDP) on IL-10 knockout mice. We administered DMDP microspheres to IL-10 KO mice rectally and assessed whether this reagent could reduce the number of local Mac-1-positive cells in the intestine and suppress the development of colitis in IL-10 KO mice. DMDP microspheres reduced the numbers of resident macrophages in the colon of IL-10 KO mice but did not reduce the percentage of Mac-1-positive cells in the spleen, peritoneal cavity, or mesenteric lymph nodes. Depletion of intestinal macrophages significantly suppressed development of chronic colitis in IL-10 KO mice, however. Third, we developed gelatin microspheres containing IL-10, which can be released sustainedly to a local site without losing bioactivity. We administered these microspheres to IL-10 KO mice rectally to investigate whether this treatment can ameliorate colitis. Colonic inflammation in mice treated with GM-IL-10 is remarkably reduced compared to those treated with IL-10 alone. Moreover, expression of CD 40 on Mac-1-positive cells treated with GM-IL-10 is decreased more notably than in mice treated with IL-10 alone. These data suggest that a drug delivery system using these microspheres containing immunomodulatory agents may be a therapeutic approach to human IBD.
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PMID:Biodegradable microspheres targeting mucosal immune-regulating cells: new approach for treatment of inflammatory bowel disease. 1269 74

Probiotic microorganisms, especially lactic acid bacteria, are effective in the treatment of infectious diarrhoeal diseases and experimental colitis. Although the mechanisms by which these organisms exert their anti-inflammatory effects are largely unknown, immunomodulating effects are suggested. The objective of this study was to examine the effect of a 5-week oral administration of Lactobacillus rhamnosus subspecies GG (Lb. GG) on the cellular immune response to intestinal microorganisms in ten healthy volunteers. Peripheral blood cells (PB) were stimulated with either 'self' or 'non-self' preparations of faecal samples and isolated Bacteroides fragilis group-organisms (Bfg) or Escherichia coli (Esch. coli), and pro- and anti-inflammatory cytokines (IL-10, IL-4, IL-6, IFN-gamma, TNF-alpha) were measured in the culture supernatant. CD4+ T-lymphocyte activation was determined by measurement of intracellular ATP following lysis of the cells. The activational response of CD4+ T-lymphocytes towards isolated and heat-inactivated intestinal organisms was increased after the probiotic treatment. Additionally, TNF-alpha, IL-6 and in part IFN-gamma cytokine secretion by PB cells following stimulation with whole stool preparations and single members of the flora was significantly decreased, whereas the IL-10 and in part IL-4 cytokine secretion was increased at the end of the study. In contrast, the activational response of CD4+ T-lymphocytes following stimulation with whole 'non-self' intestinal flora was higher than by 'self' intestinal flora, but both responses showed a trend towards a reduction at the end of the study. This study documents a direct effect by Lb. GG on the cellular immune system of healthy volunteers and offers a promising tool to investigate systemic immunomodulation due to oral administration of probiotic microorganisms.
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PMID:Immunomodulatory consequences of oral administration of Lactobacillus rhamnosus strain GG in healthy volunteers. 1280 Aug 70

CD4(+)CD25(+) regulatory T cells in normal animals are engaged in the maintenance of immunological self-tolerance and prevention of autoimmune disease. However, accumulating evidence suggests that a fraction of the peripheral CD4(+)CD25(-) T cell population also possesses regulatory activity in vivo. Recently, it has been shown glucocorticoid-induced TNFR family-related gene (GITR) is predominantly expressed on CD4(+)CD25(+) regulatory T cells. In this study, we show evidence that CD4(+)GITR(+) T cells, regardless of the CD25 expression, regulate the mucosal immune responses and intestinal inflammation. SCID mice restored with the CD4(+)GITR(-) T cell population developed wasting disease and severe chronic colitis. Cotransfer of CD4(+)GITR(+) population prevented the development of CD4(+)CD45RB(high) T cell-transferred colitis. Administration of anti-GITR mAb-induced chronic colitis in mice restored both CD45RB(high) and CD45RB(low) CD4(+) T cells. Interestingly, both CD4(+)CD25(+) and CD4(+)CD25(-) GITR(+) T cells prevented wasting disease and colitis. Furthermore, in vitro studies revealed that CD4(+)CD25(-)GITR(+) T cells as well as CD4(+)CD25(+)GITR(+) T cells expressed CTLA-4 intracellularly, showed anergic, suppressed T cell proliferation, and produced IL-10 and TGF-beta. These data suggest that GITR can be used as a specific marker for regulatory T cells controlling mucosal inflammation and also as a target for treatment of inflammatory bowel disease.
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PMID:Regulation of murine inflammatory bowel disease by CD25+ and CD25- CD4+ glucocorticoid-induced TNF receptor family-related gene+ regulatory T cells. 1284 37

CD4(+) regulatory T cells have been shown to prevent intestinal inflammation; however, it is not known whether they act to prevent the priming of colitogenic T cells or actively control these cells as part of the memory T cell pool. In this study, we describe the presence of colitogenic Th1 cells within the CD4(+)CD45RB(low) population. These pathogenic cells enrich within the CD25(-) subset and are not recent thymic emigrants. CD4(+)CD45RB(low) cells from germfree mice were significantly reduced in their ability to transfer colitis to immune deficient recipients, suggesting the presence of commensal bacteria in the donor mice drives colitogenic T cells into the Ag-experienced/memory T cell pool. This potentially pathogenic population of Ag-experienced T cells is subject to T cell-mediated regulation in vivo by both CD4(+)CD25(+) and CD4(+)CD25(-) cells in an IL-10-dependent manner. Furthermore, administration of an anti-IL-10R mAb to unmanipulated adult mice was sufficient to induce the development of colitis. Taken together, these data indicate that colitogenic Th1 cells enter into the Ag-experienced pool in normal mice, but that their function is controlled by regulatory T cells and IL-10. Interestingly, IL-10 was not absolutely required for CD4(+)CD25(+) T cell-mediated inhibition of colitis induced by transfer of naive CD4(+)CD45RB(high) cells, suggesting a differential requirement for IL-10 in the regulation of naive and Ag-experienced T cells.
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PMID:Colitogenic Th1 cells are present in the antigen-experienced T cell pool in normal mice: control by CD4+ regulatory T cells and IL-10. 1284 69

A deficiency in understanding the steps responsible for colitis is the lack of comprehension for the role chemokines play in mucosal inflammation. IFN-gamma-inducible protein-10 (IP-10) and CXCR3 are highly expressed at sites of colitis. Our findings show that IP-10 significantly contributes to the development of Th1 and inflammatory responses. Specifically, IP-10 inhibition in IL-10(-/-) mice attenuates the associated increases in serum and/or local amyloid A, IL-2, IL-6, TNF-alpha, IFN-gamma, IL-1alpha, and IL-1beta with colitis as compared with IL-10(-/-) mice that develop colitis similar to human Crohn's disease. Correspondingly, the rate or intensity of inflammation in IL-10(-/-) mice treated with anti-IP-10 Abs showed improved scoring of inflammation, compared with control IL-10(-/-) mice. This study provides important and novel information regarding IP-10 as a target for the treatment of colitis.
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PMID:Inhibition of IFN-gamma-inducible protein-10 abrogates colitis in IL-10-/- mice. 1287 31

Recombinant human granulocyte colony-stimulating factor (rhG-CSF) is an immunoregulatory drug whose effects include modulation of antigen-presentation. We investigated the potential ameliorative effect of pretreatment with rhG-CSF in a hapten-induced colitis animal model. Sprague-Dawley rats were given rhG-CSF (125 microg/kg subcutaneously twice a day for 5 days) before a colonic instillation of 2,4,6-trinitrobenzene sulfonic acid (TNBS) in 50% ethanol. Consequent colonic damage was evaluated pathologically, and cytokine mRNA expression levels in macroscopically inflamed sites were measured by real-time quantitative reverse transcription-polymerase chain reaction. Pretreatment with rhG-CSF remarkably attenuated both the loss of body weight and colonic wall thickening due to progressive transmural inflammation. In the control, treatment with TNBS led to a statistically significant (p < 0.05) upregulation of IFN-gamma mRNA expression in the inflammatory sites measured at post-treatment day 7. In the experimental group, pretreatment with rhG-CSF abrogated transcription of IFN-gamma (p < 0.05), but was not, however, associated with an upregulation of IL-4 or the regulatory cytokines TGF-beta and IL-10. Furthermore, transcription of IL-12p35 (a rate-limiting factor for the production of IL-12) was significantly (p < 0.05) downregulated by rhG-CSF at 24h post-TNBS instillation, whereas IL-12p40 was not affected. Pretreatment with rhG-CSF drastically attenuated the degree of TNBS-induced colitis through selective downregulation of Th1-associated cytokines.
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PMID:Regulation of T helper type-1 immunity in hapten-induced colitis by host pretreatment with granulocyte colony-stimulating factor. 1290 51

Regulatory CD4+ Th cells can prevent many autoimmune diseases; however, the factors selecting for these cells remain poorly defined. In transgenic mice with a mutation in the CD4 binding region on class II MHC, the disruption of CD4-class II interactions selected for CD4+ Th cells that expressed surface markers and cytokines associated with regulatory Th cells. Th cells from these mice were enriched for CD45RB(low) as well as CD25+, while they expressed high levels of the transcription factor associated with regulatory T cells, Foxp3, and cytokines, including IL-4, IL-10, and IFN-gamma mRNA and protein. These regulatory Th cells inhibited the function of APCs via IL-10 production, and adoptive transfer of these cells prevented weight loss and inflammation in a model of colitis. CD4+ regulatory Th cells emerged only when interactions between CD4 and class II MHC were deficient on cells of nonhemopoietic origin. These data support a novel model controlling the differentiation of regulatory Th cells and suggest that interactions between CD4 and class II MHC may a useful target for re-educating T cells as a treatment for inflammatory diseases.
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PMID:CD4+ Th cells resembling regulatory T cells that inhibit chronic colitis differentiate in the absence of interactions between CD4 and class II MHC. 1292 72

The present study explores the dietary effect of pectin on the MLN lymphocyte functions of mice with dextran sulfate sodium (DS)-induced colitis. We found that the immunoglobulin (Ig)A level in mesenteric lymph node (MLN) lymphocytes was high, while the IgE level was lower, in mice fed with pectin than in those fed with cellulose. Interestingly, the fecal IgA concentration of the pectin-fed mice was significantly higher than that of the cellulose-fed mice. The concentrations of interferon-gamma and interleukin (IL)-2 treated with concanavalin A (ConA) were significantly higher in the pectin-fed group than in the cellulose-fed group. Although dietary pectin did not affect the IL-4 and IL-10 levels, the activation-induced IL-4 and IL-10 secretion was lower in MLN cells of the pectin-fed mice than of the cellulose-fed mice following DS-induced colitis. Based on these findings, we propose that the effect of dietary pectin on mice with DS-induced colitis is mediated by the manipulation of Th1 cells. Furthermore, the inhibitory effect of IL-4 and IL-10 by dietary pectin may play an important role in promoting a change in Th1/Th2 balance toward Th1-dominant immunity.
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PMID:Effect of dietary pectin on the production of immunoglobulins and cytokines by mesenteric lymph node lymphocytes in mouse colitis induced with dextran sulfate sodium. 1295 3

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