UMLS:C0010346 - FACTA Search

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Query: UMLS:C0010346 (Crohn's disease)
21,615 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gamma interferon (IFN-gamma) production by peripheral blood mononuclear cells (PBM) was measured in 21 patients with Crohn's disease, in 15 patients with ulcerative colitis, in 12 patients with non-IBD gastrointestinal disease (disease control), and in 28 healthy controls. T-cell subset proportions and serum levels of thymosin alpha 1 and thymosin beta 4, two hormonelike thymic peptides, were also determined. No differences were seen in T-cell subset proportions in patients with Crohn's disease or ulcerative colitis when compared to healthy controls or to the disease-control group. In vitro IFN-gamma production was markedly decreased in Crohn's disease and in untreated, but not treated, patients with ulcerative colitis. Preincubation of PBM prior to the addition of inducer mitogen resulted in enhanced IFN-gamma production in patients with Crohn's disease or ulcerative colitis which significantly exceeded that seen either in healthy controls or in the disease-control group. Serum thymosin alpha 1 levels were comparable in all study groups; however, serum thymosin beta 4 concentrations were significantly higher in all patient groups than in the healthy controls. These results confirm a defective in vitro IFN-gamma production in patients with IBD which is apparently independent of endocrine thymus regulation.
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PMID:Defective in vitro gamma interferon production and elevated serum immunoreactive thymosin beta 4 levels in patients with inflammatory bowel disease. 312 96

Five patients with Crohn's disease (CD) confined to the small intestine were studied to determine whether intravenous administration of interferon (IFN)-gamma to normalize immunological imbalance produces clinical improvement. A daily dose of 12 million IU of IFN-gamma was intravenously infused for four weeks. Laboratory data, immunological responses, clinical and radiologic findings were evaluated after administration. Laboratory data showed no significant change after treatment. Immunological studies also failed to demonstrate any significant change except for a significant increase of natural killer (NK) cell activity after IFN-gamma infusion. Clinical assessment by Crohn's disease activity index as well as radiologic findings disclosed no definite improvement. This study suggests that enhancement of NK cell activity or augmentation of immunological imbalance induced by IFN-gamma does not play an important role in the pathogenesis of CD.
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PMID:Immunological and clinical effects of interferon-gamma on Crohn's disease. 313 10

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

The in vivo interferon (IFN) activation in Crohn's disease was evaluated by measuring the relative amounts of IFN-alpha and -gamma mRNA in freshly isolated human lamina propria mononuclear cells (LPMC) from patients with Crohn's disease and controls. Both IFN-gamma and IFN-alpha mRNA, as estimated by dot blot analysis, were increased in Crohn's disease (LPMC), although the relative amounts of IFN mRNA appeared to differ among patients. Appreciable amounts of IFN-gamma mRNA were found in Crohn's disease peripheral blood mononuclear cells (PBMC) extracts, whereas the same cells were negative for IFN-alpha mRNA. Only minute amounts of IFN-gamma RNA were found sporadically in control LPMC while no IFN-alpha was detected. Control PBMC were shown to be virtually negative for both IFN-alpha and IFN-gamma mRNA. These data suggest that IFN induction in the normal human gut is a well-controlled function and that in Crohn's disease tissues, both IFN-gamma and IFN-alpha production are dysregulated. The increased IFN activity may represent a major feature in the induction and perpetuation of the chronic inflammatory process in Crohn's disease.
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PMID:Interferon expression in Crohn's disease patients: increased interferon-gamma and -alpha mRNA in the intestinal lamina propria mononuclear cells. 786 Oct 27

Crohn's disease and ulcerative colitis are chronic inflammatory bowel diseases of unknown etiology. However, there is circumstantial evidence that immune mechanisms play an important role in the pathogenesis of the intestinal lesion, and cytokines produced by lymphoid cells may be critical for the extraintestinal sequelae of the disease. In both Crohn's disease and ulcerative colitis, activation of macrophages seems to be a key feature. Increased production of the macrophage derived cytokines TNF-alpha, IL-1 and IL-6 have been reported in both diseases. Additionally in Crohn's disease, large numbers of activated T lymphocytes can be detected in the lamina propria and the T lymphocyte derived cytokines IL-2 and IFN-gamma are secreted by a higher number of lamina propria T lymphocytes in active Crohn's disease. However, this is not the case in ulcerative colitis. The increased number of activated T lymphocytes secreting IFN-gamma may be responsible for granuloma formation in Crohn's disease, as well as for MHC class II antigen expression on colonic epithelial cells. Lamina propria T lymphocytes seem to have lost their physiological unresponsiveness to several microbial antigens. All these observations suggest that Crohn's disease may be caused by hyperreaction of the local cellular immune system to numerous microbial and nutritional antigens normally present in the intestine. The factor inducing this immune dysregulation remains unknown. Cell-mediated immunity seems to be less important in ulcerative colitis, as activated T lymphocytes are only sparse within the inflamed mucosa, and the T lymphocyte derived cytokines IL-2 and IFN-gamma cannot be detected in the gut lesion or in the serum.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Immune mechanisms in chronic inflammatory bowel disease. 810 3

Many of the in vivo activities of interferon (IFN)-gamma match the changes found in inflammatory bowel disease, but its importance is controversial. Interferon (IFN)-gamma induces the expression of B7-2 costimulatory molecules on monocytes. We measured levels of IFN-gamma production in intestinal mucosa and isolated lamina propria mononuclear cells (LPMC) in patients with Crohn's disease (CD) and ulcerative colitis (UC). We also investigated the induction of B7-2 on the LPMC by flow cytometry. Mucosal IFN-gamma production was higher than the control level in patients with CD, but this was not the case in UC. IFN-gamma production and B7-2 expression in the LPMC of CD were higher than in the LPMC of UC and controls, and high levels of B7-2 expression were observed on the LPMC of CD after incubation with endotoxin. The induction of B7-2 on the LPMC of CD may provide a mechanism for the amplification of T cell proliferation and lymphokine production by IFN-gamma-activated LPMC.
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PMID:Enhanced interferon-gamma production and B7-2 expression in isolated intestinal mononuclear cells from patients with Crohn's disease. 856 91

In this study, we investigate whether human inflammatory bowel disease (IBD) (ulcerative colitis and Crohn's disease) is associated with altered lymphokine secretion profiles, as recently found in various animal models of chronic intestinal inflammation. In initial studies, we determined the proliferative responses of purified lamina propria (LP) CD4+ T cells from patients with IBD under defined conditions of T cell stimulation. We found that IBD LP CD4+ T cells in comparison with control LP CD4+ T cells have diminished TCR/CD3 pathway proliferative responses, whereas CD2/CD28 accessory pathway proliferative responses are relatively preserved. In further studies centering on lymphokine production, we showed that LP T cells from inflamed Crohn's disease mucosa manifest increased IFN-gamma secretion compared with control LP T cells, particularly when stimulated via the CD2/CD28 pathway. Subsequent ELISPOT analysis indicated that this was due to an increased number of IFN-gamma-secreting CD4+ T cells. In contrast, IL-4 and IL-5 production by Crohn's disease LP T cells was decreased compared with that of control LP T cells. Of interest, IL-2 production by Crohn's disease LP T cells was also reduced, as was IL-2 production by peripheral blood T cells. In parallel studies, LP T cells from inflamed ulcerative colitis mucosa stimulated via either the TCR/CD3/CD28 or CD2/CD28 produced increased amounts of IL-5, again when measured either as secreted IL-5 or by ELISPOT analysis. Such increased IL-5 production was not associated with increased IL-4 secretion and, in contrast to Crohn's disease, ulcerative colitis LP T cell production of IL-2 and IFN-gamma was normal. Taken together, these studies provide strong evidence that the immunopathologic process characteristic of the two major forms of IBD is associated with very different cytokine secretion patterns. These different patterns may determine the type of inflammatory process present.
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PMID:Disparate CD4+ lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease. Crohn's disease LP cells manifest increased secretion of IFN-gamma, whereas ulcerative colitis LP cells manifest increased secretion of IL-5. 875 34

The above new findings concerning the immunological mechanisms governing mucosa, immune responses and oral tolerance in TCR-transgenic mice, as well as those operative in mice with experimental colitis, greatly expand our understanding of the processes that normally control mucosal inflammation and possibly other types of inflammation as well (Fig. 1). They indicate that, in the nondiseased mouse, ingested proteins evoke a Th1-cell (IFN-gamma) response in the mucosal follicles that is quickly counter-regulated by induction of T-cell anergy/deletion, if this Th1-cell response is inhibited (experimentally by anti-IL-12), TGF beta-producing cells appear, and these are capable of active immune suppression. This reciprocal relationship between IFN-gamma production and TGF-beta production is further supported in mouse models of mucosal inflammation. Thus, in the TNBS-colitis model, there is direct stimulation of the immune cells in the lamina propria as a result of diffuse haptenization of mucosal proteins, which leads to a massive Th1-cell response capable of overwhelming any suppressive counter-regulatory mechanisms normally generated in the PPs. This highly polarized Th1-cell response is controlled only by direct abrogation of IL-12 production with exogenous administration of anti-IL-12, or with indirect inhibition of this response via induction of oral tolerance and accompanying production of TGF-beta (Refs 6-8). The data obtained from this model are consistent with those obtained with another model of intestinal inflammation--inflammation in severe combined immunodeficiency (SCID) mice following lymphoid repletion with CD45Rbhi (naive) T cells. In this model, inflammation is again mediated by Th1 cells and is prevented by co-repletion with CD45Rbhi (memory) T cells, which appear to work by secreting TGF-beta (Refs 9, 10). Thus, a common feature of the various experimental models of intestinal inflammation studied to date is the Yin-Yang relationship of IFN-gamma and TGF-beta, with the former being proinflammatory and the latter anti-inflammatory. Is the IFN-gamma TGF-beta dichotomy that is evident both in the normal state and in models of inflammation simply a reflection of an underlying Th1 Th2 dichotomy? The answer to this important question is not yet known. Thus, while it is clear from the in vitro studies already discussed that IL-12 and/or IFN-gamma inhibit TGF-beta production, the role of IL-4 in this process is more elusive. These in vitro studies indicate that IL-4 is not required for TGF-beta production, a finding that is consistent with studies in which the transfer of CD45Rbhi, T cells from IL-4-/- mice protected SCID mice from colitis induced by CD45Rbhi T cells. However, the addition of IL-4 to in vitro cultures containing anti-IL-12 augmented TGF-beta production, most probably by IL-4 acting as a growth factor for TGF-beta-producing cells rather than as an inducing factor (T. Marth et al., unpublished). Obviously, more work will be necessary to resolve this issue. Finally, it should be noted that the above considerations apply to human inflammatory diseases of the gastrointestinal tract, such as Crohn's disease. Recently, it has been shown that T cells extracted from Crohn's disease tissues manifest skewed Th1-cell responses. The hypothesis can therefore be put forward that this disease results from a dysregulated Th1-cell response to ubiquitous mucosal antigens that is not appropriately controlled by normal counter-regulatory mechanisms. Interventions that artificially bring the excessive Th1-cell response back into balance, such as administration of IL-12 antagonists, should therefore find a central place in the treatment of the disease.
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PMID:Reciprocal IFN-gamma and TGF-beta responses regulate the occurrence of mucosal inflammation. 905 54

Lymphocyte-mediated inflammation is a hallmark of autoimmune diseases, such as multiple sclerosis. Crohn's disease, rheumatoid arthritis and sarcoidosis. However, this type of inflammation probably developed under evolutionary pressure from pathogenic microorganisms, such as mycobacteria and other intracellular infective agents. One such pathogen, the gram-positive bacterium Listeria monocytogenes (L. monocytogenes), induces a cascade of tissue alterations that ultimately results in the eradication of the bacteria associated with a granulomatous response. Consequently, murine listeriosis has been established as a model to analyze not only T-cell-dependent antibacterial protection but also T-cell-mediated mononuclear inflammation in parenchymal organs. Extensive studies of the molecular basis of the latter phenomenon led to the conclusion that the most decisive step from non-specific microabscess formation to granulomatous inflammation is the activation of non-specifically invading CD4+ T cells, which results in high local concentrations of TNF-alpha and IFN-gamma in the presence of IL-2. This in turn induces CD11b-independent mechanisms of intraparenchymal monocyte accumulation. Because any attempt to neutralize the effects of TNF-alpha and IFN-gamma to modulate T-cell-mediated inflammation will also dramatically decrease host resistance, other anti-inflammatory strategies based on the modulation of TNF-alpha and IFN-gamma-induced mechanisms of monocyte accumulation must be developed. Recalling the classical work by Dienes & Schoenheit on the induction of bacterial allergies (1), the cytokine phenotype of granuloma formation also has implications as regards the most potent adjuvant environment for the development of a T-cell response. The murine listeriosis model is the basis for all conclusions in this article on the role of cytokines in the induction and expression of T-cell-mediated inflammation and, as we will show, promises to yield still more insights into the rational design of vaccines.
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PMID:Cytokines in the induction and expression of T-cell-mediated granuloma formation and protection in the murine model of listeriosis. 931 76

Recent clinical studies of Crohn's disease patients demonstrated dramatic clinical responses following one i.v. infusion of a chimeric mAb to TNF-alpha (cA2). To assess the role of TNF-alpha in mucosal cytokine regulation, the effects of TNF-alpha on lamina propria mononuclear cell (LPMC) Th1 production were determined. Increased IFN-gamma production was demonstrated in anti-CD2-stimulated LPMC cultured in TNF-alpha. To determine the effects of cA2 on cytokine production, TNF-alpha- and IFN-gamma-producing cells were quantitated in LPMC from five Crohn's disease patients treated with cA2. In all four patients who demonstrated clinical and endoscopic improvement, decreased numbers of LPMC producing IFN-gamma and TNF-alpha following CD2/CD28 activation paralleled improvement in disease activity over 8 wk. In one patient who did not improve, increased numbers of TNF-alpha- and IFN-gamma-secreting LPMC were observed. In three of four responding patients, CD2/CD28-activated PBMC demonstrated increased IFN-gamma production over 8 wk. These observations suggest that TNF-alpha may be a cofactor for mucosal Th1 responses, and improvement in clinical parameters and intestinal inflammation induced by cA2 in Crohn's disease may be mediated by down-regulation of mucosal Th1 cytokines.
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PMID:A role for TNF-alpha and mucosal T helper-1 cytokines in the pathogenesis of Crohn's disease. 955 Apr 32

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