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)

In this study, we describe a novel murine model of chronic intestinal inflammation induced by the hapten reagent 2,4,6-trinitrobenzene sulfonic acid (TNBS). Rectal application of low doses of TNBS in BALB/c and SJL/J mice resulted in a chronic transmural colitis with severe diarrhea, weight loss, and rectal prolapse, an illness that mimics some characteristics of Crohn's disease in humans. The colon of TNBS-treated mice on day 7 was marked by infiltration of CD4+ T cells; furthermore, in situ polymerase chain reaction studies revealed high levels of interferon (IFN)-gamma mRNA in diseased colons. Isolated lamina propria (LP) CD4+ T cells from TNBS-treated mice stimulated with anti-CD3 and anti-CD28 antibodies exhibited a Th1 pattern of cytokine secretion: a 20-50-fold increase in IL-2 and IFN-gamma levels and a 5-fold decrease in IL-4 levels as compared with those of stimulated LP CD4+ T cells from control BALB/c mice. Administration of monoclonal anti-IL-12 antibodies to the TNBS-treated mice both early (at 5 d) and late (at 20 d) after induction of colitis led to a striking improvement in both the clinical and histopathological aspects of the disease and frequently abrogated the established colitis completely. Furthermore, LP CD4+ T cells isolated from anti-IL-12-treated mice failed to secrete IFN-gamma upon in vitro stimulation. In summary, the data demonstrate the pivotal role of IL-12 and IFN-gamma in a TNBS-induced murine model of chronic intestinal inflammation. Furthermore, they suggest the potential utility of anti-IL-12 antibodies in patients with Crohn's disease.
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PMID:Antibodies to interleukin 12 abrogate established experimental colitis in mice. 759 99

Normal colonic epithelial cells play an important part in the mucosal immune system and use butyrate, a bacterial fermentation product, as an important energy source. Butyrate deficiency has been associated with inflammatory bowel disease, diversion colitis, and pseudomembranous colitis. Butyrate effects on important molecules for epithelial immune functions were studied in a colonic epithelial cell line (HT-29): the constitutive and cytokine regulated expression of secretory component (poly-Ig receptor), HLA class I and II molecules, and intercellular adhesion molecule-1 (ICAM-1). Butyrate facilitated the constitutive expression of secretory component and HLA class I. Butyrate furthermore tended to enhance cytokine mediated stimulation of protein expression, although tumour necrosis factor alpha (TNF) and interleukin 4 (IL 4) responses on HLA class I and secretory component, respectively, were relatively inhibited by butyrate. Cytokine mediated accumulation in the various mRNAs usually increased even more in the presence of butyrate, with the exception of TNF response on HLA class I and secretory component mRNA concentrations. In conclusion, butyrate may substantially influence constitutive and cytokine mediated expression of molecules with immune functions in a complex and differentiated manner, and butyrate deficiencies, as seen in various clinical conditions, might influence mucosal immune responses.
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PMID:Constitutive and cytokine induced expression of HLA molecules, secretory component, and intercellular adhesion molecule-1 is modulated by butyrate in the colonic epithelial cell line HT-29. 779 24

BALB/c mice infected with the intracellular protozoan Leishmania major mount a T helper cell 2 (Th2) response that fails to control growth of the parasite and results in the development of visceral leishmaniasis. Separation of CD4+ T cells into CD45RBhigh and CD45RBlow subsets showed that the L. major-specific Th2 cells were contained within the CD45RBlow population as these cells produced high levels of antigen-specific interleukin 4 (IL-4) in vitro and transferred a nonhealing response to L. major-infected C.B-17 scid mice. In contrast, the CD45RBhighCD4+ population contained L. major-reactive cells that produced interferon gamma (IFN-gamma) in vitro and transferred a healing Th1 response to L. major-infected C.B-17 scid mice. Transfer of the Th1 response by the CD45RBhigh population was inhibited by the CD45RBlow population by a mechanism that was dependent on IL-4. These data indicate that L. major-specific Th1 cells do develop in BALB/c mice, but their functional expression is actively inhibited by production of IL-4 by Th2 cells. In this response, the suppressed Th1 cells can be phenotypically distinguished from the suppressive Th2 cells by the level of expression of CD45RB. Although the CD45RBhigh population mediated a protective response to L. major, C.B-17 scid mice restored with this population developed a severe inflammatory response in the colon that was independent of L. major infection, and was prevented by cotransfer of the CD45RBlow population. The colitis appeared to be due to a dysregulated Th1 response as anti-IFN-gamma, but not anti-IL-4, prevented it. Taken together, the data show that the CD4+ T cell population identified by high level expression of the CD45RB antigen contains cells that mediate both protective and pathogenic Th1 responses and that the reciprocal CD45RBlow population can suppress both of these responses. Whether suppression of cell-mediated immunity is beneficial or not depends on the nature of the stimulus, being deleterious during L. major infection but crucial for control of potentially pathogenic inflammatory responses developing in the gut.
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PMID:Regulatory interactions between CD45RBhigh and CD45RBlow CD4+ T cells are important for the balance between protective and pathogenic cell-mediated immunity. 790 19

The recent finding that CD40L on activated T cells induces interleukin (IL) 12 secretion in human peripheral blood monocytes in vitro suggests that the CD40L-CD40 interaction may be of importance in the priming of T helper (Th) 1-type T cells. We therefore investigated the in vivo relevance of this interaction in an experimental model for a Th1-mediated disease, the hapten reagent (2,4,6-trinitrobenzene sulfonic acid [TNBS])-induced colitis. The administration of anti-gp39 (CD40L) antibodies during the induction phase of the Th1 response prevented interferon gamma production by lamina propria CD4+ T cells and also clinical and histological evidence of disease. In contrast, the secretion of IL-4, a Th2-type cytokine, was increased after anti-gp39 treatment. In further studies we showed that the prevention of disease activity was caused by an inhibition of IL-12 secretion, as demonstrated by immunohistochemistry. In addition, the injection of recombinant IL-12 p70 heterodimer into TNBS + anti-gp39-treated mice reversed the effect of anti-gp39 and resulted in severe disease activity. When anti-gp39 was given after the disease was established, no effect on the disease activity was observed. In conclusion, we demonstrated that the CD40L-CD40 interaction is crucial for the in vivo priming of Th1 T cells via the stimulation of IL-12 secretion by antigen-presenting cells (APC).
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PMID:Blocking the CD40L-CD40 interaction in vivo specifically prevents the priming of T helper 1 cells through the inhibition of interleukin 12 secretion. 862 84

In previous studies we showed that a chronic colitis associated with a Th1 T cell response can be induced by the rectal administration of the haptenizing reagent 2,4,6-trinitrobenzene sulfonic acid (TNBS). We report here that oral administration of haptenized colonic proteins (HCP) before rectal administration of TNBS effectively suppresses the ability of the latter to induce colitis. This suppression (oral tolerance) appears to be due to the generation of mucosal T cells producing TGF-beta and Th2-type cytokines after oral HCP administration. Peyer's patch and lamina propria CD4+ T cells from HCP-fed animals stimulated with anti-CD3/anti-CD28 had a 5-10-fold increase in their production of TGF-beta and secreted increased amounts of IL-4 and IL-10 but lower levels of IFN-gamma in comparison to T cells from ovalbumin-fed control animals. In addition, the colons of HCP-fed mice showed strikingly increased TGF-beta but decreased IL-12 expression by immunohistochemical studies and isolated mononuclear cells from HCP-fed animals secreted less IL-12 heterodimer. Finally, and most importantly, the suppressive effect of orally administered HCP was abrogated by the concomitant systemic administration of anti-TGF-beta or rIL-12 suggesting a reciprocal relationship between IL-12 and TGF-beta on tolerance induction in TNBS-induced colitis. In parallel studies we demonstrated that TNBS-induced colitis can be transferred to naive recipient animals with purified CD4+ T cells from the colon of TNBS-treated animals and that such animals develop lethal pancolitis when exposed to very low doses of TNBS. Feeding of HCP suppressed this sensitivity to TNBS, indicating that oral feeding can suppress the response of pre-committed T cells in vivo. These studies suggest for the first time that TGF-beta production can abrogate experimental granulomatous colitis even after such colitis is established, and thus, that regulation of TGF-beta levels may have relevance to the treatment of human inflammatory bowel disease.
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PMID:Experimental granulomatous colitis in mice is abrogated by induction of TGF-beta-mediated oral tolerance. 867 81

A T helper type 1 (Th1)-mediated colitis with similarities to inflammatory bowel disease in humans developed in severe combined immunodeficiency mice reconstituted with CD45RB(high) CD4+ splenic T cells and could be prevented by cotransfer of CD45RB(low) CD4+ T cells. Inhibition of this Th1 response by the CD45RB(low) T cell population could be reversed in vivo by an anti-transforming growth factor (TGF) beta antibody. Interleukin (IL) 4 was not required for either the differentiation of function of protective cells as CD45RB(low) CD4+ cells from IL-4-deficient mice were fully effective. These results identify a subpopulation of peripheral CD4+ cells and TGF-beta as critical components of the natural immune regulatory mechanism, which prevents the development of pathogenic Th1 responses in the gut, and suggests that this immunoregulatory population is distinct from Th2 cells.
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PMID:A critical role for transforming growth factor-beta but not interleukin 4 in the suppression of T helper type 1-mediated colitis by CD45RB(low) CD4+ T cells. 867 88

Mice rendered deficient in the production of interleukin 10 (IL-10-/-) develop a chronic inflammatory bowel disease (IBD) that predominates in the colon and shares histopathological features with human IBD. Our aim was to identify which cell type(s) can mediate colitis in IL-10-/- mice. We detected an influx of immunoglobulin-positive cells into the colon and the presence of colon-reactive antibodies in the serum of IL-10-/- mice. To assess a pathogenic role for B cells, we generated a B cell-deficient (B-/-) strain of IL-10-/- mice. B-/-IL-10-/- mice acquired a severe colitis analogous to that IL-10-/- mice, implying that B cells were not the primary mediator of IBD in this model. A series of cell transfer experiments was performed to assess a pathogenic role for T cells. When IL-10-/- T cell-enriched lamina propria lymphocytes (LPL) or intraepithelial lymphocytes (IEL) were transferred into immunodeficient recombinase-activating gene (RAG)-2-/- recipients, a mild to severe colitis developed, depending on the cell number transferred. Lymphocytes recovered from the colon of transplanted RAG-2-/- mice with colitis were predominantly alpha beta TCR+CD4+, including a large proportion of CD4+CD8 alpha + cells. These cells were also CD45RB-/low and CD44+, indicative of an activated/memory population. Individual populations of CD4+CD8 alpha-, CD4+CD8 alpha + and CD4-CD8 alpha + T cells were then isolated from the lamina propria compartment of IL-10-/- mice and transferred into RAG-2-/- recipients. Only IL-10-/- CD4-expressing LPL, including both the CD4+CD8 alpha- and CD4+CD8 alpha + populations, induced colitis in recipient mice. Interferon-gamma, but little to no IL-4, was produced by CD4+CD8 alpha- and CD4+CD8 alpha + LPL recovered from the inflamed colons of RAG-2-/- recipients implicating alpha T helper cell 1 (TH1)-mediated response. We thus conclude that colitis in IL-10-/- mice is predominantly mediated by TH1-type alpha beta TCR+ T cells expressing CD4 alone, or in combination with the CD8 alpha molecule.
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PMID:T helper cell 1-type CD4+ T cells, but not B cells, mediate colitis in interleukin 10-deficient mice. 869 Nov 38

We report here a murine model for experimental chronic colitis where administration of trinitrobenzene sulfonic acid (TNBS) in 50% ethanol induced inflammation of large intestine in susceptible (C3H/HeJ and BALB/c) but not resistant (C57BL/6 and DBA/2) mouse strains. We queried whether mucosal trinitrophenyl (TNP)-specific B cell responses were induced in mice with TNBS-induced colitis, and if induction of tolerance to TNBS by oral administration of this hapten protected mice from development of colitis. Isotypes and subclasses of polyclonal and TNP-specific Ab-forming cells (AFC) were assessed in mucosal and peripheral lymphoid tissues of C3H/HeJ mice with TNBS-induced colitis. Increased numbers of IgA- and IgG-secreting cells were found in the inflamed colon lamina propria. Inflamed colonic tissue also contained high frequencies of IgG anti-TNP AFC (predominantly of IgG1, IgG2a, and IgG2b subclasses); however, anti-TNP responses in noninflamed mucosal tissues of mice with colitis exhibited dominant IgA and IgM with low IgG anti-TNP responses. CD4+ T cells stimulated with TNP-splenocytes produced more IFN-gamma and less IL-4, suggesting a Th1-type response. Oral administration of TNBS before induction of colitis markedly decreased mucosal anti-TNP responses and completely inhibited anti-TNP IgG2a and IgG2b responses. Control mice did not show inhibition of anti-TNP AFC responses or TNBS-induced colitis. Intracolonic sensitization of susceptible C3H/HeJ mice with TNBS induces a localized IgG anti-TNP B cell response in the inflamed tissue, whereas prior oral administration of TNBS results in unresponsiveness to this agent and protects mice from development of TNBS-induced colitis.
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PMID:Hapten-induced model of murine inflammatory bowel disease: mucosa immune responses and protection by tolerance. 875 44

Recent studies have demonstrated that the treatment of mice with anti-gp39 antibodies impairs T-cell functions in the murine collagen type II-induced arthritis model, in acute semi-allogenic graft-versus-host disease, and in the allo-specific CTL-reaction, that is, reactions that are believed to be mediated by Th1-type T cells. On the other hand, the administration of anti-gp39 antibody did not influence Th2 T-cells responses, suggesting that CD40-CD40L interactions are more crucial for Th1 than Th2 T-cell development. Recent studies also demonstrate that dendritic cells (DC) are capable of driving a Th1 T-cell response that is mediated by IL-12. In addition, stimulation of CD40 on human monocytes results in IL-12 production, suggesting that activated T cells expressing CD40L may directly induce the production of IL-12 by antigen-presenting cells, thus allowing for the generation of a Th1 T-cell response in the absence of intracellular pathogens. We investigated whether the CD40-CD40L interaction was important in the production of IL-12 by DCs in an in vitro system that allowed precise control of cytokine concentrations. Initially we showed that FACS-purified mouse spleen DCs produce high amounts of IL-12 p40 in response to CD40 crosslinking by CD40L-expressing fibroblasts. We then demonstrate that DCs also produce IL-12 p40 in a more physiologic system using purified DCs pulsed with ovalbumin (OVA) and then cultured with LECAM-1hi T cells from ovalbumin T-cell receptor transgenic mice. Finally, we show that IL-10 has a potent capacity to shut down CD40-induced IL-12 p40 secretion; and, in addition, IL-4 partially inhibits CD40-induced IL-12 p40 secretion and enhances IL-10-mediated inhibition in an additive fashion. We also investigated the in vivo relevance of this interaction in an experimental model for a Th1-mediated disease, the hapten reagent (TNBS)-induced colitis. The administration of anti-gp39 (CD40L) antibodies during the induction phase of the Th1 response completely prevented IFN-gamma production by CD4 T cells from the intestinal lamina propria and also the clinical and histological evidence of disease. In further studies we showed that the prevention of disease activity was due to an inhibition of IL-12 secretion. Thus, the injection of recombinant IL12 p75 heterodimer into TNBS + anti-gp39-treated mice reversed the effect of anti-gp39 and resulted in severe disease activity. In conclusion, these findings suggest that DCs produce IL-12 in response to CD40 signaling, that a mechanism by which IL-4 may induce Th2 development is by acting with IL-10 to inhibit IL-12 production by DCs, and that the CD40L-CD40 interaction is crucial for the IL-12-dependent priming of Th1 T cells in vivo.
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PMID:Interleukin-12 production by dendritic cells. The role of CD40-CD40L interactions in Th1 T-cell responses. 895 22

Gene-targeted mice lacking the IL-2 gene (IL-2 -/- mice) develop various forms of autoimmunity as well as severe colitis, either spontaneously in a conventional environment or after immunization with 2,4,6-trinitrophenol (TNP)-conjugated keyhole limpet hemocyanin (KLH) in a specific pathogen-free environment. We show here that the induction of colitis with TNP-KLH induces a change in the thymocyte population characterized by decreased numbers of double positive (DP; CD4+CD8+) thymocytes (IL-2 +/+, 45.2 x 10(6) vs IL-2 -/-, 23.6 x 10(6)) and increased numbers of single positive (SP; CD4+CD8- or CD4-CD8+) thymocytes (IL-2 +/+, 5.3 x 10(6) vs IL-2 -/-, 20.9 x 10(6)). The latter also bear activation markers. In addition, thymocytes from TNP-KLH-immunized IL-2 -/- mice produce more IFN-gamma and less IL-4 than similarly immunized IL-2 +/+ mice. These defects in thymocyte maturation and lymphokine production are IL-12 driven, since they are prevented when immunized IL-2 -/- mice are coadministered with anti-lL-12. Furthermore, we demonstrate that IL-2 -/- mice exhibit decreased cortical apoptosis as determined by thymocyte numbers and detection of apoptotic cells in situ. Finally, we show that colitis-inducing thymocytes are generated in the immunized IL-2 -/- thymus, since IL-2 +/+ mice develop colitis following injection of small numbers of single positive thymocytes from immunized IL-2 -/- mice but not from IL-2 +/+ mice. Taken together, these data indicate that, in the absence of IL-2, thymocyte maturation is abnormally directed by IL-12 toward the generation of mature, activated Th1-type thymocytes that are capable of mediating colitis.
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PMID:Dysregulated intrathymic development in the IL-2-deficient mouse leads to colitis-inducing thymocytes. 897 80

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