Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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

Hepatitis, proliferative typhlitis, and colitis were characterized in young adult and older SCID/NCr mice naturally infected with Helicobacter hepaticus. Liver lesions consisted of Kupffer, Ito, and oval cell hyperplasia along with multifocal to coalescing coagulative hepatocyte necrosis. Numerous Warthin-Starry-positive bacteria were observed in the parenchyma, and there were minimal to mild accumulations of monocytic cells and neutrophils. Proliferative typhlitis was characterized by moderate to marked mucosal epithelial cell hyperplasia with mild monocytic and neutrophilic infiltration. Minimal to mild colitis with mucosal epithelial cell hyperplasia of the colon was most marked in older mice. Comparable gastrointestinal lesions were not observed in uninfected control SCID/NCr mice. H. hepaticus was cultured from fetal viscera of 2 of 11 pups sampled late in gestation from infected SCID/NCr females, suggesting transplacental infection of H. hepaticus. As expected, most of the naturally infected SCID/NCr mice had no serum immunoglobulin G response against H. hepaticus. These findings contrast with those in infected immunocompetent A/JCr mice, which develop a significant immune response to H. hepaticus associated with prominent multifocal mononuclear cell infiltrates in the liver, with only rare bacteria observable at the periphery of inflammatory foci or in the biliary canaliculi. The results demonstrate that chronic inflammatory and proliferative lesions simultaneously affecting the liver, cecum, and colon are associated with natural infection of SCID/NCr mice with H. hepaticus and that lesions are progressive with age. Concurrent infection with H. hepaticus may confound studies that have been attributed to similar lesions due to other experimental manipulations of SCID/NCr mice.
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PMID:SCID/NCr mice naturally infected with Helicobacter hepaticus develop progressive hepatitis, proliferative typhlitis, and colitis. 978 60

In this review, I hope to have highlighted that cytokines are of crucial importance in the normal homeostasis of the gut immune system, the interactions of the gut immune system with enteric antigens and also in tissue injury associated with IBD. There is evidence from a number of different systems that the response to nominal non-replicating antigens, administered nasally or orally, is skewed towards a non-Th1 type of response. To say that the response is Th2, Th3 or Tr is premature. IL-10 and TGF beta seem to be important in downregulating potentially tissue-damaging Th1 responses to the normal flora and possibly food antigens. However, it need to be seen whether the mouse results also apply to humans. A consistent pattern in disease states, whether it be human or mouse, is an exaggerated Th1 type response with excess local production of IFN-gamma and TNF alpha, and its association with tissue injury. An important question to address is whether this represents a switch from the Th2, Th3, or Tr pathway towards a Th1 pathway, or whether the Th1 pathway is in fact always present in the gut, but is kept in check and non-pathogenic by regulatory cells. Equally important is the need to discover where regulation occurs: is it in the PP or the lamina propria? Intriguing results from Kronenberg and colleagues have shown that SCID mice reconstituted with CD45RBhi or CD45RBlo cells show no difference in the re-population of the gut prior to disease (ARANDA et al. 1997). The reason for colitis developing in those mice reconstituted with CD45RBhi cells is therefore more complex than merely differential re-population kinetics. No matter what the outcome is, these and other related questions dealing with the induction and expression of mucosal T-cell responses are going to produce some surprises in the next few years.
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PMID:Effector and regulatory lymphoid cells and cytokines in mucosal sites. 989 58

We generated transgenic mice for STAT-4, a regulatory protein specifically associated with IL-12 signaling, under the control of a CMV promoter. These mice expressed strikingly increased nuclear STAT-4 levels in lamina propria CD4+ T lymphocytes upon systemic administration of dinitrophenyl-keyhole limpet hemocyanin and developed chronic transmural colitis characterized by infiltrates of mainly CD4+ T lymphocytes. The latter cells produced predominantly TNF and IFN-gamma but not IL-4 upon activation with alphaCD3/CD28 or autologous bacterial Ags, consistent with a Th1-type cell response. Furthermore, chronic colitis in STAT-4 transgenic mice could be adoptively transferred to SCID mice by colonic and splenic CD4+ T cells that were activated with Ags from autologous bacterial flora. These data establish a critical molecular signaling pathway involving STAT-4 for the pathogenesis of chronic intestinal inflammation, and targeting of this pathway may be relevant for the treatment of colitis in humans.
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PMID:Cutting edge: chronic intestinal inflammation in STAT-4 transgenic mice: characterization of disease and adoptive transfer by TNF- plus IFN-gamma-producing CD4+ T cells that respond to bacterial antigens. 997 54

We studied the induction, severity and rate of progression of inflammatory bowel disease (IBD) induced in SCID mice by the adoptive transfer of low numbers of the following purified BALB/c CD4+ T cell subsets: 1) unfractionated, peripheral, small (resting), or large (activated) CD4+ T cells; 2) fractionated, peripheral, small, or large, CD45RBhigh or CD45RBlow CD4+ T cells; and 3) peripheral IL-12-unresponsive CD4+ T cells from STAT-4-deficient mice. The adoptive transfer into SCID host of comparable numbers of CD4+ T cells was used to assess the colitis-inducing potency of these subsets. Small CD45RBhigh CD4+ T lymphocytes and activated CD4+ T blasts induced early (6-12 wk posttransfer) and severe disease, while small resting and unfractionated CD4+ T cells or CD45RBlow T lymphocytes induced a late-onset disease 12-16 wk posttransfer. SCID mice transplanted with STAT-4-/- CD4+ T cells showed a late-onset IBD manifest > 20 wk posttransfer. In SCID mice with IBD transplanted with IL-12-responsive CD4+ T cells, the colonic lamina propria CD4+ T cells showed a mucosa-seeking memory/effector CD45RBlow Th1 phenotype abundantly producing IFN-gamma and TNF-alpha. In SCID mice transplanted with IL-12-unresponsive STAT-4-/- CD4+ T cells, the colonic lamina propria, mesenteric lymph node, and splenic CD4+ T cells produced very little IFN-gamma but abundant levels of TNF-alpha. The histopathologic appearance of colitis in all transplanted SCID mice was similar. These data indicate that CD45RBhigh and CD45RBlow, IL-12-responsive and IL-12-unresponsive CD4+ T lymphocytes and lymphoblasts have IBD-inducing potential though of varying potency.
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PMID:Colitis-inducing potency of CD4+ T cells in immunodeficient, adoptive hosts depends on their state of activation, IL-12 responsiveness, and CD45RB surface phenotype. 1009 33

Spontaneous colitis resembling ulcerative colitis developed in 3 of 10 independent TCR transgenic (Tg) mouse lines maintained under specific pathogen-free conditions. All three susceptible lines were CD4 lymphopenic, whereas resistant lines had normal numbers of CD4+ T cells. Thus, cytochrome c-specific 5C.C7 TCR Tg mice developed colitis only when crossed onto a SCID- or Rag-1-deficient background. A second line of lymphopenic cytochrome c-specific Tg mice bearing the AND TCR also developed colitis. In both cases, CD4+ T cells expressing the Tg-encoded TCR were preferentially activated in inflamed colons compared with lymph nodes or spleens. In contrast, Tg+CD4+ T cells remained quiescent in both inflamed and unaffected colons in another line of susceptible Tg mice carrying a TCR specific for myelin basic protein, suggesting a fortuitous cross-reactivity of the IEk-restricted cytochrome c-reactive AND and 5C.C7 TCRs with an Ag present in the gut. The percentage of CD4+ T cells expressing only endogenous TCR alpha-chains was increased consistently in inflamed colons in AND as well as 5C.C7 Rag-1-/- TCR Tg mice, suggesting that polyclonal CD4+ T cells were also involved in the pathogenesis of spontaneous colitis. Moreover, our data indicate that some alpha-chain rearrangement was still occurring in TCR Tg mice on a Rag-1-/- background, since activated CD4+ T cells expressing endogenously rearranged alpha-chains paired with the Tg-encoded beta-chain were detected consistently in the colons of such mice.
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PMID:TCR-mediated involvement of CD4+ transgenic T cells in spontaneous inflammatory bowel disease in lymphopenic mice. 1035 67

The objectives of this study were to assess the role of the inducible isoform of nitric oxide synthase (iNOS) on vascular cell adhesion molecule 1 (VCAM-1) expression in vivo in an acute model of inflammation induced in iNOS-deficient (iNOS-/-) mice and compare these data to those obtained by pharmacological inhibition of iNOS in a CD4+ T lymphocyte-dependent model of chronic colitis. VCAM-1 expression was quantified in vivo using the dual radiolabel monoclonal antibody technique. We found that intraperitoneal injection of 10 microg/kg tumor necrosis factor-alpha (TNF-alpha) enhanced VCAM-1 expression by approximately twofold in the colon, cecum, and stomach but not small intestine in iNOS-/- mice compared with TNF-alpha-injected wild-type mice. Injection of wild-type mice with 25 microg/kg TNF-alpha further enhanced VCAM-1 expression by approximately twofold compared with wild-type mice injected with 10 microg/kg TNF-alpha; however, VCAM-1 expression was not further enhanced in any gastrointestinal organ system in iNOS-/- mice. In a second series of experiments, we found that continuous inhibition of iNOS using oral administration of NG-iminoethyl-L-lysine did not alter the enhanced levels of VCAM-1 expression in the colon nor did it alter the severity of colonic inflammation in SCID mice reconstituted with CD4+, CD45RB(high) T cells. We conclude that iNOS may regulate VCAM-1 expression in acute inflammation; however, this effect is modest and tissue specific and occurs only when VCAM-1 expression is submaximal. iNOS does not appear to modulate VCAM-1 expression in an immune model of chronic colitis.
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PMID:Role of inducible nitric oxide synthase in the regulation of VCAM-1 expression in gut inflammation. 1048 82

The objective of this study was to quantify E-selectin surface expression in the colon as well as other tissues in a CD4(+) T-cell model of chronic colitis in mice using the newly developed dual radiolabel monoclonal antibody technique. Male SCID mice were reconstituted with either 5 x 10(5) CD4(+) CD45RB(low) or CD45RB(high) T-cells isolated from normal CB-17 donor mouse spleens and subsequently monitored for clinical signs of colitis. We found that animals injected with CD45RB(high) but not CD45RB(low) T-cells nor PBS developed colitis at 6-8 weeks following reconstitution as assessed by loss of body weight, development of loose stools and/or diarrhea, and histopathology. Concurrent with the onset of distal bowel inflammation was enhanced expression of E-selectin compared to SCID mice injected with PBS or reconstituted with CD45RB(low) T-cells, both of which did not develop colitis. We also observed significant increases in E-selectin expression in cecum, small intestine, mesentery, and liver of colitic mice. Our data confirm that reconstitution of SCID mice with CD45RB(high) but not CD45RB(low) T-cells induces chronic colitis and demonstrate that this chronic colitis is associated with enhanced expression of an endothelial cell-specific adhesion molecule. Furthermore, our studies demonstrate that reconstitution of SCID mice with CD45RB(high) T-cells enhances E-selectin expression in a variety of tissues distant from the site of active inflammation.
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PMID:E-Selectin expression in a murine model of chronic colitis. 1067 41

Increased expression of CD40 and CD40 ligand (CD40L or CD154) has been found in inflamed mucosa of human inflammatory bowel disease (IBD), and interactions between these molecules seem to be involved in local cytokine production by macrophages. However, the precise role of CD40 signaling in the pathogenesis of IBD is still poorly understood. The aim of the present study was to investigate the in vivo relevance of CD40 signaling in experimental colitis in SCID mice reconstituted with syngeneic CD45RBhighCD4+ T cells. The results demonstrated that CD40+ and CD40L+ cells as well as their mRNA levels were significantly increased in inflamed mucosa. Administration of anti-CD40L neutralizing mAb over an 8-wk period starting immediately after CD45RBhighCD4+ T cell reconstitution completely prevented symptoms of wasting disease. Intestinal mucosal inflammation was effectively prevented, as revealed by abrogated leukocyte infiltration and decreased CD54 expression and strongly diminished mRNA levels of the proinflammatory cytokines IFN-gamma, TNF, and IL-12. When colitic SCID mice were treated with anti-CD40L starting at 5 wk after T cell transfer up to 8 wk, this delayed treatment still led to significant clinical and histological improvement and down-regulated proinflammatory cytokine secretion. These data suggest that the CD40-CD40L interactions are essential for the Th1 inflammatory responses in the bowel in this experimental model of colitis. Blockade of CD40 signaling may be beneficial to human IBD.
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PMID:Prevention of experimental colitis in SCID mice reconstituted with CD45RBhigh CD4+ T cells by blocking the CD40-CD154 interactions. 1082 Feb 84

Inflammatory bowel disease (IBD) is associated with Th1/Th2 cytokine dysregulation, leukocyte extravasation, and tissue edema, but the mechanisms for cytokine-mediated vascular dysfunction are not understood. To investigate how cytokines might control edema in IBD, we determined vascular permeability and IFN-gamma expression in two models of murine colitis: SCID mice reconstituted with CD45RB(high T-lymphocytes (CD45RB(high)/SCID mice), and interleukin-10 gene deficient (IL-10(-/-)) mice. We also investigated the in vitro effects of IFN-gamma and IL-10 on human endothelial solute barrier and junction protein expression. Vascular permeability in CD45RB(high)/SCID and IL-10(-/-) mice was quantified using tissue (131)I-IgG accumulation. The IFN-gamma message was quantified using the ribonuclease protection assay. Endothelial barrier integrity in vitro was measured by transmonolayer electrical resistance, and junctional proteins were examined by immunoblotting and fluorescence microscopy. Both CD45RB(high)/SCID and IL-10(-/-) mice exhibit enhanced colonic microvascular leakage and IFN-gamma message levels compared to their respective controls. In vitro, IFN-gamma also reduced endothelial barrier (monolayer electrical resistance, increased albumin permeability) and reduced tight junction (occludin) expression and staining. These effects were reversed by pretreatment of monolayers with IL-10. Therefore, in vivo IFN-gamma and IL-10 may modulate microvascular leakage in IBD partly by controlling the expression of intestinal endothelial tight junctional proteins.
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PMID:Interferon-gamma and interleukin-10 reciprocally regulate endothelial junction integrity and barrier function. 1116 3

Transfer of CD45RB(high) CD4+ T cells to immune-deficient mice in the absence of regulatory T cells leads to a Th1-mediated colitis. In this study, we show that intestinal inflammation is characterized by a 15-fold increase in the number of CD134L+ (OX40L+)-activated DC in the mesenteric lymph nodes (MLNs) compared with BALB/c mice. This was important functionally, as administration of an anti-CD134L mAb inhibited the proliferation of T cells in the MLNs as well as their expression of the gut-homing integrin alpha(4)beta(7). Most importantly, the anti-CD134L mAb completely blocked development of colitis. Surprisingly, CD134L was found to be expressed by a proportion of dendritic cells (DC) in the MLNs of unreconstituted SCID mice, suggesting that CD134L can be induced on DC in the absence of T cell-derived signals. These results indicate that some DC in the MLNs of SCID mice express an activated phenotype and that CD134L expression by these cells is involved in the development of colitis induced by T cell transfer. Accumulation of CD134L+ DC was inhibited by cotransfer of regulatory T cells, suggesting that inhibition of the accumulation of activated DC is one mechanism by which these cells prevent immune pathology.
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PMID:CD134L expression on dendritic cells in the mesenteric lymph nodes drives colitis in T cell-restored SCID mice. 1135 59


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