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PubMed2003

Control of immune pathology by regulatory T cells.

CD4+CD25+ T(reg) cells inhibit colitis in the severe combined immune deficient (SCID) T cell adoptive transfer model. Cells with this function are present in the thymus suggesting that T(reg) cells capable of inhibiting bacteria-induced immune pathology are similar to those that inhibit organ-specific autoimmunity. CD4+CD25+ T(reg) cells inhibit both T cell-dependent and T cell-independent intestinal inflammation. The latter point illustrates that in addition to direct effects on other T cells, T(reg) cells can alsoprevent immune pathology in vivo by inhibiting the actions of innate immune cells. T(reg) cells suppress intestinal inflammation through mechanisms that involve interleukin 10 and transforming growth factor beta and blockade of the negative regulator of T cell activation CTLA4 abrogates T(reg) cell function in vivo. Importantly adoptive transfer of CD4+CD25+ T(reg) cells to mice with established colitis reverses inflammation and restores normal intestinal architecture suggesting that CD4+CD25+ T(reg) cells may be utilized for cellular therapy of inflammatory diseases.

Adoptive Transfer↗
PubMed2001

Disturbance of the prejunctional modulation of cholinergic neurotransmission during chronic granulomatous inflammation of the mouse ileum.

The effect of chronic granulomatous inflammation of the intestine was studied on the prejunctional modulation of cholinergic nerve activity in the mouse ileum. Contractions to carbachol (0.01 - 0.3 microM) and to electrical field stimulation (EFS, 0.25 - 8 Hz) of enteric neurons were higher in inflamed ileum as compared to control ileum. However, when the neurally-mediated contractions to EFS were expressed as percentage of the direct smooth muscle contraction to carbachol, the responses to EFS were similar in control and inflamed ileum. Atropine (1 microM) abolished all contractions to EFS and carbachol in control and inflamed ileum. DMPP (3 - 30 microM), a nicotinic receptor agonist, induced concentration-dependent contractions that were more pronounced in inflamed ileum as compared to control ileum. Hexamethonium (100 microM), a nicotinic receptor blocker, significantly inhibited the contractions to EFS in inflamed ileum but not in control ileum. In control ileum, histamine (10 - 100 microM) and the histamine H(1) receptor agonist HTMT (3 - 10 microM) inhibited the contractions to EFS concentration-dependently without affecting the contractions to carbachol. The inhibitory effect of histamine and HTMT was prevented by the histamine H(1) antagonist mepyramine (5 - 10 microM) but not by the H(2)- and H(3)-receptor antagonists cimetidine and thioperamide (both 10 microM). In chronically inflamed ileum however, histamine (10 - 100 microM) and HTMT (3 - 10 microM) failed to inhibit the contractions to EFS. The histamine H(2) and H(3) receptor agonists dimaprit and R(-)-alpha-methylhistamine did not affect the contractions to EFS in control and inflamed ileum. The alpha(2)-receptor agonist UK 14.304 (0.01 - 0.1 microM) inhibited the contractions to EFS in control and inflamed ileum without affecting the contractions to carbachol. The effect of UK 14.304 was reversed by the alpha(2)-receptor antagonist yohimbine (1 microM). The inhibitory effect of UK 14.304 on contractions to EFS was of similar potency in control and inflamed ileum. Our results suggest that the prejunctional modulation of cholinergic nerve activity by nicotinic and histaminic H(1) receptors is disturbed during chronic intestinal inflammation whereas the modulation by alpha(2)-receptors is preserved. Such a disturbance of cholinergic nerve activity may contribute to the motility disturbances that are often observed during chronic intestinal diseases in humans.

Adrenergic Agonists↗
PubMed2000

[New knowledge on the pathogenesis of chronic inflammatory bowel diseases: what have we learned from colitis animal models?].

In recent years it has been possible to establish animal models with colitis by immunological and genetic manipulation. Such animal models share characteristic features with human inflammatory bowel disease. The fact that different immune defects induce inflammation in the intestines supports the theory of heterogeneity in the pathogenesis of human inflammatory bowel disease. Discrepant results concerning the disease association with genetic markers have been obtained in different populations, which may confirm the concept of heterogeneity. So far it has not been possible to identify one single factor which is aetiologically responsible for the development of inflammatory bowel disease. The intestinal inflammation is normally T cell-dependent and caused by a dysbalance of pro- and anti-inflammatory immune responses. Interestingly, animals kept under germfree conditions do not develop disease. Thus, the intestinal bacterial flora plays a crucial role. The loss of immune tolerance towards these bacterial antigens is an important current concept in the pathogenesis of inflammatory bowel disease.

Animals↗
PubMed1991

In vitro model of intestinal crypt abscess. A novel neutrophil-derived secretagogue activity.

In order to model crypt abscesses, a histological finding which correlates with disease activity in intestinal inflammation, human polymorphonuclear leukocytes (PMN) were layered onto monolayers of the human intestinal epithelial cell line T84, a crypt-like epithelium which is capable of Cl- secretion. Such PMN-epithelial interaction had no substantial effect on monolayer integrity or function. However, when PMN were stimulated by conditions including those present naturally in the human colonic lumen, monolayers responded with a bumetanide-sensitive short circuit current (Isc) indicative of Cl- secretion, the basis of secretory diarrhea. This Isc response was induced by a neutrophil-derived secretagogue (NDS), which was only active when applied to the luminal surface of monolayers and did not require PMN-epithelial contact. NDS activity is resistant to boiling, acid, and trypsin and passes a 500 nominal mol wt cutoff filter. NDS activity is not secondary to the respiratory burst products O2- or H2O2 and does not appear to be a myeloperoxidase product. We speculate NDS elicited Cl- secretion may contribute to the secretory diarrhea seen in patients with intestinal inflammation and crypt abscesses.

Abscess↗
PubMed2006

CD4+CD25+ cell depletion from the normal CD4+ T cell pool prevents tolerance toward the intestinal flora and leads to chronic colitis in immunodeficient mice.

BACKGROUND: CD4+CD25+ regulatory T cells have been shown to prevent immune-mediated colitis in mice; however, it is unclear whether the absence of CD4+CD25+ in the normal CD4+ T cell pool is responsible for the development of chronic colitis. Using the T cell-deficient Tgepsilon26 mouse model, we show that CD4+CD25- cells but not CD4+CD25+ cells induce a severe intestinal inflammation. Transfer of CD4+CD25+ cells, together with CD4+CD25- cells, ameliorated intestinal inflammation, and reconstitution with the whole mesenteric lymph node cell pool did not induce colitis in recipients. Transferred CD4+CD25- cells were found mainly in the mesenteric lymph nodes, where they showed an activated TH1-like phenotype. In the absence of regulatory CD4+CD25+ T cells, recipient CD4 cells secreted IFN-gamma in response to stimulation with intestinal bacterial antigen that was prevented in vivo and in vitro by regulatory CD4+CD25+ cells. These studies suggest that CD4+CD25- cells have a strong colitogenic effect in the Tgepsilon26 colitis model and that CD4+CD25+ cells may be the main regulators that prevent or downregulate the proinflammatory effect of colitogenic T cells in the Tgepsilon26 mouse model.

Animals↗
PubMed1996

Selective kallikrein-kinin system activation in inbred rats differentially susceptible to granulomatous enterocolitis.

BACKGROUND & AIMS: Crohn's disease is characterized by unrestrained inflammation with a genetic component. Genetic susceptibility and activation of the kalli-krein-kinin (contact) system were investigated in experimental enterocolitis and extraintestinal inflammation induced by bacterial polymers. METHODS: Kinetics of inflammation in inbred Lewis and Buffalo rats injected subserosally with peptidoglycan-polysaccharide polymers were correlated with in vivo and in vitro activation of the contact system. RESULTS: Lewis rats had a biphasic course of enterocolitis. Acute inflammation peaked 1 day after injection, gradually decreasing until day 14 when intestinal inflammation spontaneously reactivated and persisted for 16 weeks, accompanied by arthritis, granulomatous hepatitis, anemia, and leukocytosis. Self-limited acute enterocolitis in Buffalo rats resolved by 24 days without extraintestinal involvement. Consumption of the precursor proteins prekalli-krein and high-molecular-weight kininogen indicated activation of the plasma contact system in Lewis rats and closely correlated with chronic intestinal inflammation. Contact system activation did not occur in Buffalo rats, even during acute inflammation. In vitro studies showed a decreased rate of kininogen cleavage in Buffalo plasma. CONCLUSIONS: Selective in vivo and in vitro activation of the contact system in susceptible Lewis rats suggests that this pathway is one determinant of genetic susceptibility to granulomatous enterocolitis and systemic complications.

Acute-Phase Proteins↗
PubMed1998

The pathogenesis of mucosal inflammation in murine models of inflammatory bowel disease and Crohn disease.

In recent years, it has become apparent that overproduction of the Th1 cytokines interleukin-12 and interferon-gamma is the probable driving force behind murine models of intestinal inflammation resembling Crohn disease and intestinal inflammation in humans with Crohn disease. In addition, studies of murine models strongly suggest that this overproduction is associated with inadequate secretion of the counter-regulatory and anti-inflammatory cytokine transforming growth factor-beta. Thus, mucosal inflammation in models (and possibly in humans) may result from an imbalance between normally occurring positive (immunogenic or inflammatory) responses and negative (tolerogenic or anti-inflammatory) mucosal immune responses. These new findings and the hypotheses that arise from them are being used to construct new approaches to the treatment of Crohn disease that are based on the administration of anti-inflammatory cytokines and anti-cytokine antibodies.

Animals↗
PubMed2000

Suppression of food intake is linked to enteric inflammation in nematode-infected rats.

Our aim was to investigate the cause-effect relationship between intestinal inflammation induced by infection with enteric stages of Trichinella spiralis and decreased host food intake. A suppression of food intake in T. spiralis-infected rats occurred within the first 24 h postinfection (PI) and was maximized by day 6 PI. Food intake, cumulated over an 8-day PI period, decreased by 59% compared with uninfected animals. The anti-inflammatory glucocorticoid betamethasone 21-phosphate was orally administered to rats in their drinking water to suppress T. spiralis-induced jejunal inflammation. When treated with a low dose of glucocorticoid (5.2 microg/ml), food intake in infected rats was still significantly reduced, but only by 21% compared with glucocorticoid-treated, uninfected rats. At the highest glucocorticoid dose (10.4 microg/ml) administered, infection-induced reduction in food intake was not different from that of glucocorticoid-treated, uninfected counterparts. The elevation in jejunal myeloperoxidase activity caused by infection was also significantly blunted by oral glucocorticoid treatment. Our results suggest that suppressed host food intake during enteric T. spiralis infection is directly linked to intestinal inflammation.

Administration, Oral↗
PubMed2002

Colorectal cancer in inflammatory bowel disease: molecular and clinical features.

The two forms of inflammatory bowel disease (IBD), Crohn's disease and ulcerative colitis, are characterized by chronic and relapsing inflammation of the intestines. Initiating events presumably occur well before patients are symptomatic. Evidence gathered over the past decade from both IBD patients and animal models of intestinal inflammation have confirmed that IBD represents complex heterogenic forms of diseases, influenced by a combination of environmental, genetic, and immunologic factors working in concert to produce exaggerated immune responses, resulting in chronic and remitting inflammation.

Animals↗
PubMed2002

Review article: monitoring the activity of Crohn's disease.

Crohn's disease is characterized by a chronic inflammation of the intestine of unknown aetiology. One of the main problems when treating patients with Crohn's disease, is the identification of patients undergoing early clinical relapse, for timely treatment and the possible prevention of complications. No sub-clinical markers are currently available that predict relapse during remission. Several parameters have been proposed for this purpose. Although none have proven useful, growing evidence suggests a possible benefit in the clinical management of Crohn's disease. Among these, we may identify: clinical behaviour, the characteristics of the host, clinical activity, markers of intestinal inflammation and markers of immune activation. In particular, the possible relationship between cytokine pattern and the clinical behaviour of Crohn's disease has been addressed. Overall, these observations suggest that mucosal immune activation is a feature of Crohn's disease, and may persist in the form of activated immunocompetent cells during remission. On the basis of this evidence, studies are currently investigating whether the down-regulation of immune activation markers is associated with clinical remission in Crohn's disease. It has been shown that higher mucosal levels of TNF-alpha and an increased state of activation of lamina propria mononuclear cells in patients with inactive Crohn's disease, are significantly associated with an earlier clinical relapse of the disease. These observations suggest that a persistent local immune activation during remission may represent a marker of early clinical relapse of Crohn's disease.

Biomarkers↗
PubMed2005

IgM: mucosal response in acute diarrhoeal disease of infants.

OBJECTIVE: Investigating the secretory immune response during the acute phase of diarrhoeal disease is hampered by difficulty in collecting suitable control specimens. This is particularly the case in infants, as they are the most severely affected by this disease. In this study we examined the mucosal immunoglobulin response during the acute phase of diarrhoeal disease in infants. MATERIAL AND METHODS: The intestinal outputs of secretory immunoglobulins (IgA, IgM) and non-secretory proteins (IgG, albumin, A1AT, eosinophil cationic protein (ECP)) were measured in 14 African children with acute watery diarrhoea (less than 3 days). These data were compared with those of 38 controls from the same area who had undergone whole-gut lavage (WGL) (inducing non-pathogenic watery diarrhoea) in a previous study of intestinal immunity and inflammation. Intestinal secretion rates were measured by multiplying the concentration of the substances by the rate of administration of WGL fluid (equal to the output) or by the output of diarrhoea. Statistical comparison was made using the Mann-Whitney U-test. RESULTS: IgA output in subjects with diarrhoea was 1.8-fold greater (80.7 versus 45.6 mg/kg/day, p=0.03), whereas IgM output was 10-fold greater (21 versus 2.1 mg/kg/day, p=0.0001). Albumin, A1AT and IgG were all also greater to varying degrees (2.5-6.8-fold). ECP was unchanged. Increases in the non-secretory proteins would suggest increased permeability of the gastrointestinal tract but transudation of serum was insufficient to explain the rise in immunoglobulin output. CONCLUSIONS: The 10-fold increase in IgM secretion compared with a smaller relative increase in IgA suggests that this is the primary mucosal immune response in acute diarrhoeal disease.

Biomarkers↗
PubMed1999

Early events in the pathogenesis of avian salmonellosis.

Salmonellae are gastrointestinal pathogens of man and animals. However, strains that are host-specific avian pathogens are often avirulent in mammals, and those which are nonspecific are commensal in poultry. The objective of this study was to determine whether host specificity was exhibited by bacterial abilities to invade epithelial cells or resist leukocyte killing. In this study, leukocytes isolated from humans and chickens were used to kill Salmonella in vitro. Both Salmonella pullorum, an avian-specific serotype, and Salmonella typhimurium, a broad-host-range serotype, were sensitive to killing by polymorphonuclear leukocytes isolated from both species. Both serotypes replicated in cells of the MQ-NCSU avian-macrophage cell line. In contrast, S. pullorum was noninvasive for cultured epithelial Henle 407, chick kidney, chick ovary, and budgerigar abdominal tumor cells. In the bird challenge, however, S. typhimurium rapidly caused inflammation of the intestinal mucosa, but S. pullorum preferentially targeted the bursa of Fabricius prior to eliciting intestinal inflammation. Salmonella serotypes which cause typhoid fever in mice have been shown to target the gut-associated lymphoid tissue. Observations from this study show that S. pullorum initiated a route of infection in chicks comparable to the route it takes in cases of enteric fever.

Animals↗
PubMed2001

Fibromyalgia and chronic widespread pain in patients with inflammatory bowel disease: a cross sectional population survey.

OBJECTIVE: To assess the prevalence of fibromyalgia (FM) and chronic widespread pain (CWP) in a population based cohort of patients with inflammatory bowel disease (IBD). METHODS: Patients in a prospective survey on newly diagnosed IBD were, 5 years after study entry, invited to a clinical examination including the investigation of musculoskeletal manifestations. A total of 521 patients were examined, corresponding to 80% of surviving cases with definite diagnoses of ulcerative colitis (UC) and Crohn's disease (CD). The diagnoses of FM and CWP strictly followed the American College of Rheumatology classification criteria of 1990. RESULTS: At clinical examination, FM was diagnosed in 18 patients (3.5%), 3.7% with UC and 3.0% with CD. The prevalence was 6.4% in females and 0.4% in males. Thirty-eight patients (7.3%) had CWP (8.5% with UC; 4.8% with CD). The female:male ratio was 27:3 in the UC group and 8:0 in CD. In 19 patients (50%), CWP occurred after onset of IBD. No correlation with the extent of intestinal inflammation and the occurrence of FM and CWP was found. CONCLUSION: The prevalences of FM and CWP in patients with IBD were similar to those of the general population. There were no differences in prevalence of FM and CWP between UC and CD. Chronic idiopathic inflammation of the intestine does not appear to predispose to chronic widespread pain.

Adolescent↗
PubMed2006

[Blastocystis hominis and bowel diseases].

Blastocystis hominis (B. hominis) is a parasite of uncertain role in human disease. It may be identified during a workup for gastrointestinal symptoms, usually in stools. The clinical consequences of B. hominis infection are mainly diarrhea and abdominal pain as well as nonspecific gastrointestinal symptoms such as nausea, anorexia, vomiting, weight loss, lassitude, dizziness, and flatulence. Case reports and series have suggested a pathogenic role of B. hominis in causing intestinal inflammation. Also some studies have suggested that inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) are associated with B. hominis infection. The investigators indicate that the stools of all patients presenting with IBD or IBS should be examined, and culture methods for B. hominis carried out. Invasion and mucosal inflammation of the intestine with B. hominis have been observed in studies of gnotobiotic guinea pigs. The transmission, pathogenicity, culture characteristics, taxonomy, life cycle, biochemistry and molecular biology of B. hominis remain unclear. More studies are necessary for this parasite.

Abdominal Pain↗
PubMed1986

Effect of non-steroidal anti-inflammatory drugs on the human small intestine.

The suggestion that the intestinal mucosa may be abnormally permeable and thus a site of antigen absorption in rheumatoid arthritis was tested by a 51Cr EDTA intestinal permeability test. Twelve patients with rheumatoid arthritis untreated by non-steroidal anti-inflammatory drugs (NSAIDs) had normal test results, while 12 NSAID-treated patients had increased intestinal permeability. Ten volunteers ingested aspirin, ibuprofen and indomethacin 8 and 1 hours before the study. The increased intestinal permeability was proportional to drug potency to inhibit cyclo-oxygenase. Intestinal permeability also increased following an indomethacin suppository, which suggests that the effect is systemically mediated. 111Indium leucocyte scintigrams and faecal collection showed no evidence of intestinal inflammation in 9 patients untreated by NSAIDs. Twenty-nine of 53 NSAID-treated patients showed abnormal localisation of 111indium in the right iliac fossa at 20 hours, and 32 of 49 patients had increased faecal excretion of 111indium. A 99mTc-porphyrin scan suggested that the main site of NSAID-induced intestinal inflammation was the small bowel. NSAIDs are thus shown to disrupt intestinal integrity and long term treatment leads to inflammation of the small intestine.

Anti-Inflammatory Agents, Non-Steroidal↗