Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0010346 (Crohn's disease)
 21,615 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cortistatin is a recently discovered cyclic neuropeptide related to somatostatin that has emerged as a potential endogenous antiinflammatory factor based on its production by, and binding to, immune cells. Crohn's disease is a chronic debilitating disease characterized by severe T helper 1 (Th1)-driven inflammation of the gastrointestinal tract. The aim of this study is to investigate the therapeutic effect of cortistatin in a murine model of colitis. Cortistatin treatment significantly ameliorated the clinical and histopathologic severity of the inflammatory colitis, abrogating body weight loss, diarrhea, and inflammation and increased the survival rate of the colitic mice. The therapeutic effect was associated with down-regulation of inflammatory and Th1-driven autoimmune response, including the regulation of a wide spectrum of inflammatory mediators. In addition, a partial involvement of regulatory IL-10-secreting T cells in this therapeutic effect was demonstrated. Importantly, cortistatin treatment was therapeutically effective in established colitis and avoided the recurrence of the disease. This work identifies cortistatin as an antiinflammatory factor with the capacity to deactivate the intestinal inflammatory response and restore mucosal immune tolerance at multiple levels. Consequently, cortistatin represents a multistep therapeutic approach for the treatment of Crohn's disease and other Th1-mediated inflammatory diseases.
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PMID:Cortistatin, an antiinflammatory peptide with therapeutic action in inflammatory bowel disease. 1653 13

The authors have previously reported the derivation of colonic subepithelial myofibroblasts (SEMFs) in both humans and mice from bone marrow (BM). In the pathogenesis of inflammatory bowel disease (IBD), such as Crohn's disease and ulcerative colitis, colonic SEMFs mediate several types of inflammatory response. In the present study, interleukin (IL)-10-/- mice were used as a model of IBD to investigate the involvement of BM-derived cells in the inflamed mucosa. Male whole BM [either C57/BL10 (wild type: WT) or IL-10-/- donor mice] was used to perform bone marrow transplantation (BMT) into both WT and IL-10-/- female mice. Tissue samples were evaluated by immunohistochemistry for alpha-smooth muscle actin expression and by in situ hybridization using a Y-chromosome-specific probe to track the donor-derived colonic SEMFs. The mucosal expression of mRNA for pro-inflammatory cytokines was analysed by reverse transcriptase-polymerase chain reaction (RT-PCR). In addition, mRNA expression of matrix metalloproteinase (MMP)-7 and osteopontin in the inflamed mucosa was assessed using in situ hybridization. Body weights and histological scores showed that IL-10-/- mice that received WT BM had an improved course of colitis, decreased mucosal pro-inflammatory mRNA expression, and up to 30% of their SEMFs were of BM origin. Conversely, IL-10-/- mice receiving IL-10-/- BM progressed to extensive colitis, and Y probe analysis revealed that up to 45% of colonic SEMFs were of BM origin. WT mice receiving IL-10-/- or WT BM had no signs of colonic inflammation. The expression of MMP-7 and osteopontin was up-regulated in the inflamed mucosa. In conclusion, IL-10-/- mice displayed ameliorated disease activity after WT BMT, whilst colitis was not induced in WT mice by IL-10-/- BMT. The contribution of BM-derived cells to colonic SEMFs was significantly increased in the inflamed mucosa compared with non-inflamed mucosa.
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PMID:Bone marrow transplantation ameliorates pathology in interleukin-10 knockout colitic mice. 1655 Jun 33

Uncontrolled mucosal immunity in the gastrointestinal tract of humans results in chronic inflammatory bowel disease (IBD), such as Crohn disease and ulcerative colitis. In early clinical trials as well as in animal models, IL-12 has been implicated as a major mediator of these diseases based on the ability of anti-p40 mAb treatment to reverse intestinal inflammation. The cytokine IL-23 shares the same p40 subunit with IL-12, and the anti-p40 mAbs used in human and mouse IBD studies neutralized the activities of both IL-12 and IL-23. IL-10-deficient mice spontaneously develop enterocolitis. To determine how IL-23 contributes to intestinal inflammation, we studied the disease susceptibility in the absence of either IL-23 or IL-12 in this model, as well as the ability of recombinant IL-23 to exacerbate IBD induced by T cell transfer. Our study shows that in these models, IL-23 is essential for manifestation of chronic intestinal inflammation, whereas IL-12 is not. A critical target of IL-23 is a unique subset of tissue-homing memory T cells, which are specifically activated by IL-23 to produce the proinflammatory mediators IL-17 and IL-6. This pathway may be responsible for chronic intestinal inflammation as well as other chronic autoimmune inflammatory diseases.
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PMID:IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. 1667 Jul 70

An expansion of both circulating and intestinal lamina propria CD4+ CD45RO+ T cells has been described in patients with Crohn's disease. We studied both the cytokine profile and the expression of adhesion molecules on this T-cell subset. Peripheral blood CD4+ CD45RO+ T cells from patients with Crohn's disease (n=45) were assessed by flow cytometry and RT-PCR methods. The cytokine profile was also measured in intestinal lamina propria from seven patients. They were classified according to the CDAI and the results were compared with those of patients with ulcerative colitis (n=21) and noninflammatory intestinal conditions (n=15), and healthy controls (n=39). The mean percentage of circulating CD4+ CD45RO+ T cells producing intracellular TNF was higher in active than in inactive Crohn's disease patients (p < 0.001), active (p = 0.49) and inactive ulcerative colitis (p = 0.019), and healthy controls (p =0. 017). TNF expression correlated with CDAI (p < 0.001). An increased expression of intracellular IL-2, IL-6, and IL-10 in active Crohn's disease patients was also found. CD62L was downregulated in active Crohn's disease patients while no differences were observed in CD49d and CD11a expression. Lamina propria CD4+ CD45RO+ T cells from active Crohn's disease lesions showed an increased intracellular staining of TNF, IFN-gamma, and IL-10. Both peripheral and intestinal mucosa CD4+ CD45RO+ T cells from active Crohn's disease patients show an increased production of TNF. In addition, the circulating CD4+ CD45RO+ T-cell subset expresses a pattern of adhesion molecules that promotes homing to extranodal lymphoid tissues. This T-cell subset may play a relevant role in the immunopathogenesis of Crohn's disease.
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PMID:Distinctive pattern of cytokine production and adhesion molecule expression in peripheral blood memory CD4+ T cells from patients with active Crohn's disease. 1678 63

The better understanding of the mechanisms of inflammatory bowel disease has driven our progress into the development of new biological therapies targeting specific molecules. Anti-TNF-alpha biologic compounds have shown great efficacy particularly in Crohn's disease. Infliximab (an IgG1 mouse/human chimeric monoclonal anti-TNF-alpha antibody fragment) is the most efficacious compound in induction and maintenance therapy of active and fistulizing Crohn's disease, being at present the only biological compound approved for therapy, but with the limit of the immunogenicity; CDP-571 (a humanized anti-TNF-alpha antibody) and CDP-870 (a PEGylated anti-TNF-alpha antibody) are less immunogenic, showed some efficacy in induction therapy in Crohn's disease but a rapid loss of response in maintenance therapy. Etanercept and onercept (soluble human recombinant TNF-alpha receptors fusion proteins) seem not to be efficacious in Crohn's disease demonstrating no class-effect for anti-TNF-alpha compounds. In preliminary study, adalimumab (an IgG1 humanized monoclonal anti-TNF-alpha antibody) offers good perspective of efficacy and safety also in infliximab-resistant or allergic patients. Inhibition of lymphocyte trafficking to the gut, through anti-adhesion molecules specific therapies (natalizumab, MLN-02, alicaforsen), has shown promising results: unfortunately, natalizumab, the most effective drug of this class, has recently been suspected to favour serious neurological complications. Other biologic therapies are under evaluation but at present seem to be less promising than infliximab; they consist of antiinflammatory cytokines, inhibitors of proinflammatory cytokines, hormones and growth factors: anti-IL12-antibody, interferon-alpha, interferon-beta, G-CSF, GM-CSF, EGF, growth hormone, anti-interferon-gamma, anti-IL-18, anti-IL-2-receptor and anti-CD3 antibodies. The evaluation of other biological drugs has been suspended for severe side effects as happened for anti-CD40L antibody causing thromboembolism and anti-CD4 antibody causing ly.mphopenia. Other compounds as IL-10 and IL-11 have been proven to be ineffective even if an oral formulation of IL-11 is under evaluation. Among the MAP kinases inhibitors BIRB-796 and RDP58 showed to be ineffective while CNI-1493 is under evaluation. The effort in identifying specific patients features predicting therapy response and the possible combination of different biological therapies represent undoubtedly a very promising perspective. Aim of this article is to review the biological compounds and their efficacy in IBD.
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PMID:Biological therapies for inflammatory bowel disease: research drives clinics. 1684 27

A typical feature of Crohn's disease (CD) patients is the development of antibodies against self- (PAB) or exogenous (ASCA) antigens, a process in which mucosal cytokine expression pattern might be involved. On the other hand, mutations in CARD15, a genetic risk factor for CD, alter cytokine production in response to bacterial infection. In the present study, we evaluated the role of functionally relevant IL-10 and TNFalpha gene polymorphisms in the synthesis of these antibodies and their relationship with CARD15 mutations. In CARD15 wild type patients, high TNFalpha producer genotypes protect against IgA-ASCA development, whereas an inverse association was observed in autoantibody synthesis (PAB). These associations were not observed in patients with CARD15 mutations, probably due to the lack of TNFalpha release as a consequence of the failure of CARD15 protein to recognize the peptidoglycan. Thus, we proposed a CARD15-TNFalpha circuit that might play a role in mucosal immune surveillance.
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PMID:TNFalpha genotype influences development of IgA-ASCA antibodies in Crohn's disease patients with CARD15 wild type. 1695 84

CD4+CD25+ regulatory T cells can prevent and resolve intestinal inflammation in the murine T cell transfer model of colitis. Using Foxp3 as a marker of regulatory T cell activity, we now provide a comprehensive analysis of the in vivo distribution of Foxp3+CD4+CD25+ cells in wild-type mice, and during cure of experimental colitis. In both cases, Foxp3+CD4+CD25+ cells were found to accumulate in the colon and secondary lymphoid organs. Importantly, Foxp3+ cells were present at increased density in colon samples from patients with ulcerative colitis or Crohn's disease, suggesting similarities in the behavior of murine and human regulatory cells under inflammatory conditions. Cure of murine colitis was dependent on the presence of IL-10, and IL-10-producing CD4+CD25+ T cells were enriched within the colon during cure of colitis and also under steady state conditions. Our data indicate that although CD4+CD25+ T cells expressing Foxp3 are present within both lymphoid organs and the colon, subsets of IL-10-producing CD4+CD25+ T cells are present mainly within the intestinal lamina propria suggesting compartmentalization of the regulatory T cell response at effector sites.
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PMID:Characterization of Foxp3+CD4+CD25+ and IL-10-secreting CD4+CD25+ T cells during cure of colitis. 1705 9

Functional human proteins are constitutively produced in genetically modified bacteria that survive on human mucosal surfaces, to the benefit of the host. The successful Phase I clinical trial with IL-10-producing Lactococcus lactis for Crohn's disease has opened new avenues for the use of transgenic bacteria as delivery vehicles. The major advantage of this novel strategy is the avoidance of systemic side effects associated with conventional therapies. This methodology opens up an alternative method for local delivery of therapeutic proteins to various mucosal tissues.
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PMID:Transgenic probiotica as drug delivery systems: the golden bullet? 1718 57

Inflammatory bowel disease (IBD) represents a spectrum of diseases in which inflammation leads to acute and chronic gut injury. It is a growing health issue for which no cure exists. The pathogenesis is multifactorial with links to infectious and environmental events that trigger disease in genetically predisposed individuals. Treatment of the two major forms of IBD, Crohn's disease and ulcerative colitis, involves the reduction of inflammation with toxic immunosuppressive drugs or blocking of the pro-inflammatory effects of tumour necrosis factor-alpha (TNF-alpha) with antibodies. Here, we show that the oral administration of transgenic low-alkaloid tobacco expressing the contra-inflammatory cytokine human interleukin-10 (hIL-10) reduces the severity of colitis by down-regulating TNF-alpha expression directly at the sites of inflammation in IBD-susceptible IL-10(-/-) mice. hIL-10 expressed in plants is biologically active and displays resistance to gastrointestinal degradation. Dietary supplementation with plant tissue delivering up to 9 microg of hIL-10 daily for 4 weeks was well tolerated by treated mice. Gut histology was significantly improved relative to controls (P = 0.002), and was correlated with a decrease in small bowel TNF-alpha mRNA levels and an increase in IL-2 and IL-1beta mRNA levels. Transgenic plants expressing IL-10 to directly attenuate TNF-alpha expression at sites of inflammation in the gut may become a useful new approach in the luminal therapy of IBD.
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PMID:Therapeutic effectiveness of orally administered transgenic low-alkaloid tobacco expressing human interleukin-10 in a mouse model of colitis. 1720 56

In their review, the authors state that the very low incidence and prevalence of IBD in sub-Saharan Africa cannot be explained by genetic factors since in Black populations of the U.S.A. and U.K., the incidence of these diseases is approaching that of the white populations. Beside helminths whose intestinal infestation is frequent in sub-Saharan Africa, other micro-organisms such as atypical mycobacteria, lactobacilli, etc, might have been reduced in Western population. This is a new variant of the Hygiene hypothesis. After Rook et al., these micro-organisms were acting as adjuvants for induction of T regulatory cells which, associated with antigen-presenting cells secrete IL-10 and TGF-beta, inhibiting the maturation of CD4 T cells to Th1 and Th2 effector cells, and consequently reducing the occurrence of Th1-mediated diseases like Crohn's disease and Th2-mediated diseases like ulcerative colitis. The effects of intestinal helminths on host immunity have been studied in Ethiopian Jews emigrated to Israel. Thorough studies before and after deworming have demonstrated that chronic helminth infestation provokes a state of chronic immune activation with anergy, reversible after deworming. Administration of ova of Trichuris suis, an helminth non pathogenic in man, has given encouraging results in the treatment o Crohn's disease and ulcerative colitis with a good safety record but long-term trials are needed since the potentially harmful effects of helminths on immunity.
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PMID:Intestinal helminths: a clue explaining the low incidence of inflammatory bowel diseases in Subsaharan Africa? Potential benefits and hazards of helminth therapy. 1963 90


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