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)

Rats transgenic for HLA-B27/human beta2-microglobulin develop a spontaneous multisystem inflammatory disorder that closely mimics human spondyloarthropathies. Prominent features of this disorder are gut inflammation that predominates in the colon, and arthritis. Several mediators such as IFN-gamma, IL-1beta, TNF-alpha, and inducible nitric oxide synthase (iNOS) have been found increased in the inflamed colonic mucosa. In the colon of HLA-B27 transgenic rats, iNOS is predominantly expressed by epithelial cells, and iNOS transcripts are detected in the hip cartilage of those rats, but not in nontransgenic littermates. The role of iNOS in this disorder was evaluated by administering the corticosteroid dexamethasone, or the NOS inhibitor L-N6-(1-iminoethyl)lysine (L-NIL) to HLA-B27 transgenic rats with established disease. Treatment with dexamethasone attenuated some aspects of gut inflammation, although it had no effect on iNOS expression. In contrast, treatment with L-NIL effectively inhibited iNOS activity, and resulted in an increase in colitis. Cytokine transcripts in the colon were modified by these treatments: IFN-gamma and IL-1beta were decreased after dexamethasone treatment, whereas administration of L-NIL resulted in decreased IFN-gamma, and TNF-alpha. A trend towards increased IL-1b expression was observed which could have contributed to the L-NIL pro-inflammatory effect. These results suggest that iNOS exerts a protective effect on colitis, in the inflammatory disorder of HLA-B27 transgenic rats.
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PMID:Inducible nitric oxide synthase attenuates chronic colitis in human histocompatibility antigen HLA-B27/human beta2 microglobulin transgenic rats. 1128 54

The class I MHC allele HLA-B27 is highly associated with the human spondyloarthropathies, but the basis for this association remains poorly understood. Transgenic rats with high expression of HLA-B27 develop a multisystem inflammatory disease that includes arthritis and colitis. To investigate whether CD8alphabeta T cells are needed in this disease, we depleted these cells in B27 transgenic rats before the onset of disease by adult thymectomy plus short-term anti-CD8alpha mAb treatment. This treatment induced profound, sustained depletion of CD8alphabeta T cells, but failed to suppress either colitis or arthritis. To address the role of CD8alpha(+)beta(-) cells, we studied four additional groups of B27 transgenic rats treated with: 1) continuous anti-CD8alpha mAb, 2) continuous isotype-matched control mAb, 3) the thymectomy/pulse anti-CD8alpha regimen, or 4) no treatment. Arthritis occurred in approximately 40% of each group, but was most significantly reduced in severity in the anti-CD8alpha-treated group. In addition to CD8alphabeta T cells, two sizeable CD8alpha(+)beta(-) non-T cell populations were also reduced by the anti-CD8alpha treatment: 1) NK cells, and 2) a CD4(+)CD8(+)CD11b/c(+)CD161a(+)CD172a(+) monocyte population that became expanded in diseased B27 transgenic rats. These data indicate that HLA-B27-retricted CD8(+) T cells are unlikely to serve as effector cells in the transgenic rat model of HLA-B27-associated disease, in opposition to a commonly invoked hypothesis concerning the role of B27 in the spondyloarthropathies. The data also suggest that one or more populations of CD8alpha(+)beta(-) non-T cells may play a role in the arthritis that occurs in these rats.
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PMID:CD8 alpha beta T cells are not essential to the pathogenesis of arthritis or colitis in HLA-B27 transgenic rats. 1251 79

Rats on Lewis or Fischer background, transgenic for human HLA-B27 and beta(2)-microglobulin genes spontaneously develop colitis, gastritis, arthritis, dermatitis, orchitis, epididymitis, carditis, alopecia and nail changes. Disease susceptibility correlates with the gene copy number and is influenced by the genetic background. The pathomechanism in this model is still not completely understood. Cell transfer experiments indicate an essential role of HLA-B27 expression in bone marrow-derived cells. On Fischer background the onset of colitis occurs at 2 months of age, peaks at 3 months of age, and plateaus. Histologic findings include inflammatory cell infiltration, mostly limited to the mucosa, crypt hyperplasia, reduction of goblet cells, occasionally crypt abscesses and early ulcers. There is evidence that normal luminal bacteria play an essential role in initiating and perpetuating chronic colitis and gastritis in HLA-B27 transgenic rats: Transgenic rats raised under germ-free conditions do not develop gastrointestinal disease, whereas transgenic littermates exposed to specific pathogen-free bacteria develop colitis and gastritis within 2-4 weeks. Obligate anaerobic bacteria, especially Bacteroides spp., may play a predominant role since metronidazole prevents colitis and transgenic germ-free rats contaminated with a cocktail of six obligate and facultative anaerobic bacteria develop colitis and gastritis only in the presence of Bacteroides vulgatus. Luminal bacteria may also be involved in trafficking and homing of inflammatory cells into remote organs, since varying cecal bacterial composition does not only alter local inflammation but also influences gastritis. Lymphocyte transfer experiments indicate a specific response to luminal bacteria. In summary, this animal model is suitable for investigating the influence of normal luminal bacteria on the cellular immune mechanism in chronic intestinal inflammation.
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PMID:Role of commensal bacteria in chronic experimental colitis: lessons from the HLA-B27 transgenic rat. 1257 16

Inflammatory bowel diseases (IBDs) are associated with an increased whole-body protein turnover. In certain drug-induced experimental models of IBD, disturbances of protein synthesis in tissues have been reported recently, but it is unclear if similar disturbances occur in other chronic intestinal diseases. Therefore we investigated changes in protein synthesis in different tissues of HLA-B27 (human leucocyte antigen B27) transgenic rats that develop spontaneously chronic inflammation, with major involvement of the colon. Protein synthesis rate in HLA-B27 rats was shown to be higher in nine different tissues compared with control (Fisher 344) rats. The absolute rate of protein synthesis was highly stimulated at the main inflammatory site (+290% in the colon). However, liver, muscle and skin appeared to be major contributors to the increased protein synthesis observed at the whole-body level. Despite the increased protein synthesis, HLA-B27 rats presented a marked atrophy of muscles, which suggests an increased proteolysis. These results contrast with metabolic disturbances described in acute inflammation and colitis induced by drugs (i.e. dextran sodium sulphate). The present study suggests that the modifications of protein metabolism are strongly influenced by the type of the inflammatory diseases and thus by the underlying mechanisms, which result in different metabolic adaptations and specific nutritional requirements.
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PMID:Increased tissue protein synthesis during spontaneous inflammatory bowel disease in HLA-B27 rats. 1279 56

The pathogenesis of inflammatory bowel diseases (IBD) proceeds through stages of initiation, amplification and healing. Abundant clinical and experimental data incriminate luminal bacteria or bacterial products in both the initiation and perpetuation of chronic intestinal inflammation. Macrophage and T-cell activation with accompanying inflammatory cytokine production appears to be an early event. Studies of lymphocyte responsiveness to autologous and heterologous intestinal bacteria have suggested that this activation may result from a breakdown in tolerance to the enteric flora in IBD. This lack of tolerance might be due to an imbalance between protective and aggressive commensal luminal bacterial species (dysbiosis), a decreased barrier function and/or an impaired mucosal clearance allowing the access of bacteria to the mucosal immune system and lack of regulatory mediators or cells. There is still controversy over whether the virulence traits of bacteria are expressed broadly or just in a small subset of bacteria. Individual bacterial species within the indigenous flora vary in their capacity to drive intestinal inflammation. In experimental models, some bacteria such as Bacteroides vulgatus can cause colitis alone when monoassociated in the HLA-B27 transgenic rat model. Others, including Lactobacillus and Bifidobacterium species have no proinflammatory capacity and have been used as probiotics. In patients with IBD, systematic approach to this issue is hampered by the limited knowledge of intestinal flora. Adherent-invasive Escherichia coli are a possible candidate for the onset and/or persistence of intestinal inflammation in patients with Crohn's disease, since they possess all the virulence factors that allow the bacteria to cross the intestinal barrier, to move to deep tissues, and to continuously activate macrophages. The recent identification of NOD2/CARD15 as a susceptibility gene for Crohn's disease has provided another link between the immune response to enteric bacteria and the development of mucosal inflammation. NOD2/CARD15 is composed of two caspase recruitment domain (CARD), a nucleotide-binding domain (NBD) and a leucin-rich-repeat (LRR) region. The LRR domain of NOD2/CARD15 has binding activity for bacterial peptidoglycans and its deletion stimulates the NF-kappaB pathway. The most frequent variants of NOD2/CARD15 observed in Crohn's disease tend to cluster in the LRR and its adjacent regions. This suggests that the LRR domain of CD-associated variants is likely to be impaired in its recognition of microbial components. Continuing studies are investigating the pathophysiological mechanisms induced by NOD2/CARD15 variants in the intestinal mucosa.
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PMID:[Intestinal flora and Crohn's disease]. 1284 62

Recombinant human interleukin (IL)-11 is a pleiotropic cytokine with anti-inflammatory activity. The objective of the study was to investigate whether oral treatment with rhIL-11 improves colonic epithelial dysfunction in the human leukocyte antigen (HLA)-B27 transgenic rat model of spontaneous chronic inflammation. Experiments were performed using adult male HLAB27 rats, whereas healthy nontransgenic F344 rats served as controls. Enteric-coated rhIL-11 multi-particles (equivalent to 500 microg/kg rhIL11) or placebo (formulation lacking rhIL-11) were administrated orally on alternate days for 2 weeks to HLA-B27 or F344 rats. Stool character was observed daily during the treatment period. Animals were euthanized at the end of treatment and colonic inflammation was evaluated be measuring tissue myeloperoxidase (MPO) activity. Epithelial transport in isolated colonic mucosal sheets was studied in modified Ussing chambers. Oral treatment of HLA-B27 rats with rhIL-11 reduced MPO activity in the colon and suppressed the clinical signs of diarrhea. The electrophysiological characteristics of mucosal transport were improved in the HLA-B27 rats treated with rhIL-11 compared with placebo. After rhIL-11 treatment the basal transepithelial resistance and the estimated paracellular resistance were significantly increased, neurally mediated secretory responses to electrical field stimulation were improved, and cholinoceptor sensitivity was normalized. Treatment with rhIL-11 had no significant effect on basal short circuit current and the maximal secretory response to carbachol or substance P. Our data demonstrate that oral rhIL-11 therapy is associated with suppression of mucosal inflammation and a concomitant improvement of epithelial resistance and neurally mediated secretion in a model of chronic HLA-B27 colitis.
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PMID:Oral treatment with recombinant human interleukin-11 improves mucosal transport in the colon of human leukocyte antigen-B27 transgenic rats. 1456 59

Germ-free HLA-B27 transgenic (TG) rats do not develop colitis, but colonization with specific pathogen-free (SPF) bacteria induces colitis accompanied by immune activation. To study host-dependent immune responses to commensal caecal bacteria we investigated cytokine profiles in mesenteric lymph node (MLN) cells from HLA-B27 TG versus nontransgenic (non-TG) littermates after in vitro stimulation with caecal bacterial lysates (CBL). Supernatants from CBL-stimulated unseparated T- or B- cell-depleted MLN cells from HLA-B27 TG and non-TG littermates were analysed for IFN-gamma, IL-12, TNF, IL-10 and TGF-beta production. Our results show that unfractionated TG MLN cells stimulated with CBL produced more IFN-gamma, IL-12 and TNF than did non-TG MLN cells. In contrast, CBL-stimulated non-TG MLN cells produced more IL-10 and TGF-beta. T cell depletion abolished IFN-gamma and decreased IL-12 production, but did not affect IL-10 and TGF-beta production. Conversely, neither IL-10 nor TGF-beta was produced in cultures of B cell-depleted MLN. In addition, CD4(+) T cells enriched from MLN of HLA-B27 TG but not from non-TG rats produced IFN-gamma when cocultured with CBL-pulsed antigen presenting cells from non-TG rats. Interestingly, IL-10 and TGF-beta, but not IFN-gamma, IL-12 and TNF were produced by MLN cells from germ-free TG rats. These results indicate that the colitis that develops in SPF HLA-B27 TG rats is accompanied by activation of IFN-gamma-producing CD4(+) T cells that respond to commensal bacteria. However, B cell cytokine production in response to components of commensal intestinal microorganisms occurs in the absence of intestinal inflammation.
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PMID:Reduced ratio of protective versus proinflammatory cytokine responses to commensal bacteria in HLA-B27 transgenic rats. 1503 May 11

HLA-B27 transgenic rats spontaneously developing a chronic inflammation mainly involving the colon are recognized as a powerful animal model for IBD. We investigated the mucin production in 6-month-old HLA-B27 rats by measuring in vivo fractional synthesis rate (FSR) and expression of mucins. In the inflamed colon of HLA-B27 rats, the mucin FSR was stimulated by 75% compared to F-344 controls, while MUC2,3 mRNA expression was unchanged. A local depletion in mucus-containing goblet cells was observed, suggesting a rapid mucin production/release and/or a real global decrease in goblet cell number. In the noninflamed jejunum of HLA-B27 rats, the mucin FSR was reduced by 35% compared to controls, while MUC2,3 mRNA expression was unchanged. Different alterations in mucin metabolism and expression are observed between HLA-B27 rats and a model of chemically induced chronic colitis (DSS-treated rats), suggesting that mucin alterations may be dependent on the animal model and colitis underlying mechanism.
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PMID:The chronic colitis developed by HLA-B27 transgenic rats is associated with altered in vivo mucin synthesis. 1510 81

An overly aggressive immune response to the intestinal microflora in a genetically susceptible host background has been implicated in the pathogenesis of inflammatory bowel diseases. We measured the impact of a probiotic preparation (SIM) containing inulin on the severity of colitis and on intestinal microflora profiles of HLA-B27-beta(2)-microglobulin transgenic (TG) rats. SIM is a mixture of lactobacilli, bifidobacteria, and inulin. Two-month-old TG rats received either SIM or water. Control TG rats received metronidazole, alone or in combination with SIM, for 8 weeks. Nontransgenic rats received SIM or water. The cecal content was removed for analysis of the intestinal microflora by PCR combined with denaturing gradient gel electrophoresis. The colon was scored for histological evidence of inflammation, colonic myeloperoxidase activity and interleukin-1beta RNA levels were measured photometrically or by real-time quantitative PCR. At 4 months, the colonic inflammation of TG rats treated with SIM was histologically diminished compared to that in untreated TG rats (2.2 +/- 0.2 versus 2.9 +/- 0.1; P </= 0.03). The administration of SIM altered the microflora profiles of TG rats by increasing the diversity and stimulating specifically the growth of Bifidobacterium animalis. The probiotic bacteria added to SIM were below the detection level in cecal stool samples at the end of the study period. The administration of SIM resulted in a measurable impact on the cecal microflora profiles of TG rats with attenuation of colitis. The lack of detection of any added probiotic bacteria in the cecal content suggests that prebiotic inulin is the major effective compound.
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PMID:Effects of feeding a probiotic preparation (SIM) containing inulin on the severity of colitis and on the composition of the intestinal microflora in HLA-B27 transgenic rats. 1513 86

HLA-B27/beta2 microglobulin transgenic (TG) rats spontaneously develop T-cell-mediated colitis when colonized with normal commensal bacteria, but remain disease-free under germ-free conditions. We investigated regulation of in vitro T-cell responses to enteric bacterial components. Bacterial lysates prepared from the caecal contents of specific pathogen-free (SPF) rats stimulated interferon-gamma (IFN-gamma) production by TG but not non-TG mesenteric lymph node (MLN) cells. In contrast, essentially equivalent amounts of interleukin-10 (IL-10) were produced by TG and non-TG cells. However, when cells from MLNs of non-TG rats were cocultured with TG MLN cells, no suppression of IFN-gamma production was noted. Both non-TG and TG antigen-presenting cells (APC) pulsed with caecal bacterial lysate were able to induce IFN-gamma production by TG CD4+ cells, although non-TG APC were more efficient than TG APC. Interestingly, the addition of exogenous IL-10 inhibited non-TG APC but not TG APC stimulation of IFN-gamma production by cocultured TG CD4+ lymphocytes. Conversely, in the presence of exogenous IFN-gamma, production of IL-10 was significantly lower in the supernatants of TG compared to non-TG APC cultures. We conclude that commensal luminal bacterial components induce exaggerated in vitro IFN-gamma responses in HLA-B27 TG T cells, which may in turn inhibit the production of regulatory molecules, such as IL-10. Alterations in the production of IFN-gamma, and in responses to this cytokine, as well as possible resistance of TG cells to suppressive regulation could together contribute to the development of chronic colitis in TG rats.
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PMID:Dysregulated luminal bacterial antigen-specific T-cell responses and antigen-presenting cell function in HLA-B27 transgenic rats with chronic colitis. 1610 23


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