[Perspectives of studying the indicators of cellular hypersensitivity in ulcerative colitis].
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Cell Migration Inhibition↗
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Results for “Colitis, Lymphocytic”
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Immunohistochemical studies of the formation and epithelial transport of immunoglobulins in normal and diseased human intestinal mucosa.
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Agammaglobulinemia↗
Interleukin 7 transgenic mice develop chronic colitis with decreased interleukin 7 protein accumulation in the colonic mucosa.
We have demonstrated that intestinal epithelial cells produce interleukin 7 (IL-7), and IL-7 serves as a potent regulatory factor for proliferation of intestinal mucosal lymphocytes expressing functional IL-7 receptor. To clarify the mechanism by which locally produced IL-7 regulates the mucosal lymphocytes, we investigated IL-7 transgenic mice. Here we report that transgenic mice expressing murine IL-7 cDNA driver by the SRalpha promoter developed chronic colitis in concert with the expression of SRalpha/IL-7 transgene in the colonic mucosa. IL-7 transgenic but not littermate mice developed chronic colitis at 4-12 wk of age, with histopathological similarity to ulcerative colitis in humans. Southern blot hybridization and competitive PCR demonstrated that the expression of IL-7 messenger RNA was increased in the colonic mucosal lymphocytes but not in the colonic epithelial cells. IL-7 protein accumulation was decreased in the goblet cell-depleted colonic epithelium in the transgenic mice. Immunohistochemical and cytokine production analysis showed that lymphoid infiltrates in the lamina propria were dominated by T helper cell type 1 CD4+ T cells. Flow cytometric analysis demonstrated that CD4+ intraepithelial T cells were increased, but T cell receptor gamma/delta T cells and CD8alpha/alpha cells were not increased in the area of chronic inflammation. Increased IL-7 receptor expression in mucosal lymphocytes was demonstrated in the transgenic mice. These findings suggest that chronic inflammation in the colonic mucosa may be mediated by dysregulation of colonic epithelial cell-derived IL-7, and this murine model of chronic colitis may contribute to the understanding of the pathogenesis of human inflammatory bowel disease.
Animals↗
Altered immune responses in interleukin 10 transgenic mice.
Interleukin (IL)-10 is a pleiotropic cytokine which inhibits a broad array of immune parameters including T helper cell type 1 (Th1) cytokine production, antigen presentation, and antigen-specific T cell proliferation. To understand the consequences of altered expression of IL-10 in immune models of autoimmune disease, the response to infectious agents, and the response to tumors, we developed transgenic mice expressing IL-10 under the control of the IL-2 promoter. Upon in vitro stimulation, spleen cells from unimmunized transgenic mice secrete higher levels of IL-10 and lower amounts of IFN-gamma than do controls, although no gross abnormalities were detected in lymphocyte populations or serum Ig levels. Transfer of normally pathogenic CD4(+) CD45RBhigh splenic T cells from IL-10 transgenic mice did not cause colitis in recipient severe combined immunodeficiency mice. Furthermore, co-transfer of these transgenic cells with CD4(+) CD45RBhigh T cells from control mice prevented disease. Transgenic mice retained their resistance to Leishmania major infection, indicating that their cell-mediated immune responses were not globally suppressed. Lastly, in comparison to controls, IL-10 transgenic mice were unable to limit the growth of immunogenic tumors. Administration of blocking IL-10 mAbs restored in vivo antitumor responses in the transgenic mice. These results demonstrate that a single alteration in the T cell cytokine profile can lead to dramatic changes in immune responses in a manner that is stimulus dependent. These mice will be useful in defining differences in inflammatory conditions and cellular immunity mediated by IL-10.
Animals↗
[Local distribution of T lymphocyte subsets in non-specific inflammatory bowel disease].
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Adolescent↗
T-cellular immune reactions (in macrophage inhibition factor assay) against Mycobacterium paratuberculosis, Mycobacterium kansasii, Mycobacterium tuberculosis, Mycobacterium avium in patients with chronic inflammatory bowel disease.
A mycobacterial aetiology has been suggested for Crohn's disease. A slow growing mycobacterium, biochemically and genetically identical to M paratuberculosis, the causative agent of enteritis in ruminants (Johne's disease), has been isolated from gut specimens of patients affected by Crohn's disease. If M paratuberculosis or other mycobacteria play a role in the pathogenesis of Crohn's disease, then patients may have been sensitised to these mycobacteria or show an anergy immune reaction. We therefore investigated the T-cell mediated immune response to sonicates of M paratuberculosis, M kansasii, M avium, and M tuberculosis in 35 patients with Crohn's disease, 28 with ulcerative colitis, and 25 controls using a macrophage inhibition factor assay on peripheral blood lymphocytes. Two types of reaction patterns were identified--that is, 'responders' (subjects with a macrophage inhibition factor assay in which a dose response relation was present and a percentage of inhibition exceeding 20%), and 'non-responders'. There was no significant difference in the prevalence of responders (59%-80%) and non-responders (20%-41%) to these mycobacteria between the group of Crohn's disease, ulcerative colitis, and control group. We found also that a large proportion of controls showed T-cell immunisation to the mycobacteria which supports the contention that the antigens are practically commensal. Our results do not support the proposed involvement of mycobacteria in the pathogenesis of Crohn's disease.
Adult↗
[Avid E-rosetting lymphocytes and T-cell subsets in inflammatory bowel disease].
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Colitis, Ulcerative↗
Effect of cyclosporin A on cell adhesion molecules and leukocyte-endothelial cell interactions in experimental colitis.
BACKGROUND: Cyclosporin A (CsA) is an immunosuppressive agent that is believed to act primarily through effects on T-helper lymphocyte function and proliferation. The aim of this study was to investigate whether modulation of leukocyte recruitment and expression of cell adhesion molecules contribute to the therapeutic efficacy of CsA in a model of experimental colitis. METHODS: The therapeutic effects of CsA were assessed in mice with dextran sulfate sodium-induced colitis. Leukocyte-endothelial cell interactions were determined in colonic venules by intravital microscopy. The expression of cell adhesion molecules intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and mucosal addressin cell adhesion molecule 1 (MAd-CAM-1) was measured by the radiolabeled antibody technique. RESULTS: Treatment with CsA (4 mg/kg/day) significantly improved the clinical course of colitis, decreasing weight loss, diarrhea, rectal bleeding, disease activity index, colon weight, and colonic shortening. Microscopic damage score, myeloperoxidase activity, tumor necrosis factor alpha (TNF-alpha), and interleukin-6 in colonic tissue were significantly diminished by CsA. CsA also significantly reduced ICAM-1 and VCAM-1, but not MAdCAM-1, expression in colitic mice. TNF-alpha-induced ICAM-1 and VCAM-1 expression in primary cultures of human umbilical vein endothelial cells was reduced by co-incubation with CsA. The reduction in adhesion molecule expression was followed by a marked decrease in leukocyte adhesion in colonic venules of colitic mice. CONCLUSIONS: CsA ameliorates experimental colitis in mice. Reduced adhesion molecule expression resulting from diminished pro-inflammatory cytokine production and from a direct effect of CsA in endothelial cells decreases leukocyte recruitment into the inflamed intestine, contributing to this protective effect.
Animals↗
An inverse correlation of human peripheral blood regulatory T cell frequency with the disease activity of ulcerative colitis.
Evidence suggests that CD4+CD25+ regulatory T cells play a crucial role in the suppression of intestinal inflammation. However, their role in the suppression of inflammatory bowel disease has not yet been addressed. We examined the proportion of regulatory T cells in inflammatory bowel disease. First, we isolated CD4+CD45RO+CD25+ T cells from the peripheral blood of healthy persons and showed that these cells suppressed T cell proliferation profoundly and expressed FoxP3 abundantly, revealing that they are regulatory cells. Then the proportion of CD45RO+CD25+ in peripheral blood CD4+ T cells was analyzed in patients and healthy controls by flow cytometry. CD4+CD45RO+CD25+ T cell frequency was significantly lower in active ulcerative colitis than in the control and inactive ulcerative colitis. CD4+CD45RO+CD25+ T cell frequency was inversely correlated with the clinical and endoscopic severity of ulcerative colitis. These results suggest that a deficiency of regulatory T cells is associated with the progression of ulcerative colitis.
Adolescent↗
Exacerbated colitis associated with elevated levels of activated CD4+ T cells in TCRalpha chain transgenic mice.
BACKGROUND AND AIMS: An unconventional CD4+ TCRalpha(-)beta(+) cell population mediates the development of colitis resembling ulcerative colitis in T-cell receptor alpha mutant (TCRalpha(-/-)) mice. However, the significance of such T cells in individuals with an intact TCRalpha locus remains unclear. Because a substantial proportion of naturally rearranged TCRalpha chains fails to pair with TCRbeta chains, the aim of this study was to analyze the development of CD4+ TCRalpha(-)beta(+) cells and the course of colitis in the presence of such a TCRalpha chain. METHODS: TCR chain transgenic TCRalpha(-/-) mice were generated and compared with wild-type and TCRalpha(-/-) mice by flow cytometric analysis of T lymphocytes with respect to their TCR expression and activation status and by histological analysis of colon tissue. The colitogenic potential of the unconventional CD4+ TCRalpha(-)beta(+) cells was assessed by adoptive transfer experiments. Furthermore, the half-life of TCRbeta chains was determined by pulse-chase labeling and immunoprecipitation. RESULTS: Transgenic expression of a TCR Valpha7.2 chain led to increased frequencies of CD4+ TCRalpha(-)beta(+) cells that caused rapid onset of colitis, reminiscent of, but even more severe than, that in TCRalpha(-/-) mice. This unconventional T-cell population displayed a constitutively activated phenotype in normal and transgenic TCRalpha(-/-) mice. An extended half-life of newly synthesized TCRbeta chains suggests a chaperone function of the TCR Valpha7.2 chain in TCRalpha(-/-) mice. CONCLUSIONS: Physiological TCRalpha rearrangement can promote the formation of chronically activated CD4+ TCRalpha(-)beta(+) T cells and may play a role in the etiology of UC.
Adoptive Transfer↗
Protective effects of Polygalae root in experimental TNBS-induced colitis in mice.
In this study, the protective effect of Polygalae root was evaluated in a murine model of experimental colitis by intrarectal injection with 2,4,6-trinitrobenzene sulfonic acid (TNBS). Polygalae root, given orally at 2, 4 g/kg body weight of herbs once a day consecutively for 9 days, could recover the lost body weight and decrease the gross rectal bleeding. Polygalae root also reduced the degree of inflammation and improved significantly the histological changes such as infiltration by polymorphonuclear leukocytes and multiple erosive lesions. Furthermore, the cytokine production of intraepithelial lymphocytes was analyzed. The results showed that IFN-gamma was increased, but IL-4 was decreased in TNBS-induced colitis, when those were compared with the sham controls. But the administration of Polygalae root to TNBS-induced colitis mice showed lower production of IFN-gamma and higher production of IL-4 than the TNBS-induced colitis. These results suggest that the protective effects of Polygalae root against the TNBS colitis may be associated with the regulation of cytokine production of intraepithelial lymphocytes.
Animals↗
CD44 isoform expression on colonic epithelium mediates lamina propria lymphocyte adhesion and is controlled by Th1 and Th2 cytokines.
BACKGROUND AND AIMS: CD44v6 and CD44v3 are expressed on the surface of colonic epithelial cells in ulcerative colitis to a much greater extent than in Crohn's disease. We investigated mediators that induce CD44v6 and CD44v3 expression on colonic epithelium and the potential role of CD44 in mediating leucocyte-epithelial adhesion. DESIGN AND METHODS: HT-29 cells were exposed to a range of T-helper 1 and T-helper 2 cytokines. Flow cytometry was used to determine their effect on CD44 isoform expression. The adhesion of peripheral blood and lamina propria lymphocytes to HT-29 monolayers was assessed and the effect of induction and blocking of CD44 isoforms was investigated. RESULTS: Treatment of HT-29 cells with IL-4 and IL-13 resulted in a two- to three-fold increase in membrane expression of CD44v6 and CD44v3 isoforms. This was inhibited by T-helper 1 cytokines and hydrocortisone (P < 0.001). IL-4 increased lymphocyte adhesion to HT-29 monolayers approximately two-fold (P < 0.01). This increased adhesion of both lamina propria leucocytes and peripheral blood lymphocytes was abolished by anti-CD44v6 monoclonal antibodies (P < 0.01 and P < 0.05, respectively). CONCLUSION: IL-4 and IL-13 are potent inducers of CD44v6 and CD44v3 expression on colon epithelial cells. The reciprocal effects of T-helper 2 and T-helper 1 cytokines on CD44 isoform expression may explain the observed differences between ulcerative colitis and colonic Crohn's disease. We have identified increased adhesion between lymphocytes and colon epithelial cells caused by IL-4-induced CD44v6 expression. This may contribute to epithelial targeting of inflammation in ulcerative colitis.
Basement Membrane↗
The colitis of Behçet's syndrome.
A 29-year-old woman with Behçet's syndrome developed a severe colitis that ultimately required colectomy. The colectomy specimen showed extensive mucosal ulceration with varying longitudinal, fissuring, and aphthoid configurations, usually occurring within a background of normal or focally inflamed mucosa, and associated with a lymphocytic vasculitis involving submucosal veins. A review of the literature reveals 29 additional cases of colitis complicating Behçet's syndrome. The colitis is characterized by multiple ulcers of diverse size, appearance, and depth of penetration involving any portion of the large bowel, occasionally with coexistent ileal or anal disease. Vasculitis may be the underlying process. Although it resembles other types of colitis, particularly Crohn's colitis, differences in clinical and pathologic features suggest that the colitis of Behçet's syndrome represents a distinct condition.
Adult↗
Acute dilation of the colon in malignant lymphoma.
Acute dilatation of the colon with signs of systemic toxicity developed in an elderly man with malignant lymphoma. Although barium contrast X-rays taken previously were interpreted as consistent with granulomatous colitis, rectal biopsy had revealed features characteristic of malignant lymphoma, poorly differentiated lymphocytic type. Bone marrow and lymph nodes were also involved. The onset of dilatation was temporally related to therapy with opiates and anticholinergics, and the acute episode was resolved with nasogastric suction, intravenous fluids, albumin, and antibiotics.
Aged↗
Oral administration of unmodified colonic but not small intestinal antigens protects rats from hapten-induced colitis.
Colonic administration of a hapten, 2,4,6-trinitrobenzene sulphonic acid (TNBS) has been shown to induce colitis in rats. We are using this model to investigate the role of colonic antigens in the immunopathology. In this study, we show that colitis can be suppressed by oral administration of haptenized colonic antigens prior to the TNBS enema. Moreover, our data suggest that haptenization of the colonic antigens is not essential because oral feeding of non haptenized colonic antigens too protects rats from TNBS-induced colitis. Thus, unmodified colonic antigens may be involved in the induction of oral tolerance, and possibly in the pathogenesis in this model of colitis. Further, we show that the protective immunity or oral tolerance induced by non haptenized colonic antigens can be passively transferred to naïve rats by mesenteric T lymphocytes. Interestingly, oral feeding of small intestinal antigens, haptenized and non haptenized, does not protect rats from colitis, suggesting a specific role for colonic antigens. These data underscore the usefulness of this rat model in the identification of pathogenic antigens in colitis and in the development of therapeutic strategies based on oral tolerance.
Administration, Oral↗
Alteration in T lymphocyte subpopulations in inflammatory bowel disease.
Peripheral blood mononuclear cells from thirty-one patients with inflammatory bowel disease (ulcerative colitis and Crohn's disease) were analysed for the proportions and absolute numbers of total T cells, and for the T cell subpopulations carrying Fc receptors for either IgM (Tmu cells) or IgG (T gamma cells). Twenty-six control subjects were studied simultaneously. Total T cell numbers were normal in patients with inflammatory bowel disease but there was a marked reduction in the proportion and absolute numbers of Tmu cells in patients, whether their disease was active or in remission. T gamma cells were normal. Simultaneous assessment of lymphocyte response to mitogens in vitro was performed in a group of patients. Responses to phytohaemagglutinin, concanavalin A and pokeweed mitogen were decreased and a positive correlation was found between the number of circulating Tmu cells and the responses to mitogens in vitro. These studies demonstrate that despite the presence of normal numbers of total T cells in inflammatory bowel disease, there is a marked imbalance in T cell subpopulations that correlates with mitogen responsiveness. This imbalance provides a possible cellular basis for the defect in cell-mediated immunity seen in these patients.
Adolescent↗
Peripheral blood mononuclear-cell interleukin-2 production, receptor generation and lymphokine-activated cytotoxicity in inflammatory bowel disease.
The interleukin-2 pathway is essential for the normal immune response to antigen stimulation; we have examined the possibility that this may underlie abnormal peripheral blood lymphocyte immunoregulatory function that has been observed in patients with inflammatory bowel disease. We studied 11 patients with Crohn's disease and 5 with ulcerative colitis, all with quiescent disease activity. Peripheral blood mononuclear cells were isolated from these patients and from healthy age- and sex-matched controls. Interleukin-2 production after mitogen and phorbol-myristate acetate stimulation was similar in both groups: 381 +/- 71 (mean +/- SE) U/ml by control cells and 451 +/- 70 by patient cells. Interleukin-2 receptor generation was also measured pre- and poststimulation by labeling with anti-Tac antibody. This was 10.45 +/- 1 and 69.95 +/- 3.85% for control cells and 11.41 +/- 1.38 and 60.9 +/- 4.25% for patients cells. Finally, we examined the response of these cells to interleukin-2 stimulation by generating cells with direct cytotoxicity to 51Cr-labeled Daudi-cell targets. Control cells caused 59.5 +/- 46% 51Cr release, whereas patient cells caused 50.8 +/- 5.18% release. None of the above results achieved statistical significance. We conclude that the peripheral blood interleukin-2 pathway is normal in inactive inflammatory bowel disease.
Cells, Cultured↗