Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021390 (inflammatory bowel disease)
 23,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A patient with glycogen storage disease (GSD) type Ib, neutrophenia, chronic inflammatory bowel disease and recurrent abscesses was treated with recombinant human granulocyte-macrophage colony stimulating factor (GM-CSF). GM-CSF (and also granulocyte colony stimulating factor) therapy markedly increased the neutrophil counts and reduced the frequency of infections and inflammation. We conclude that myeloid growth factors are effective for the treatment and prevention of acute infections and chronic inflammatory complications in patients with GSD Ib.
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PMID:Glycogen storage disease type Ib: infectious complications and measures for prevention. 768 91

Ulcerative colitis (UC) and Crohn's disease (CD) are immunologically mediated disorders characterized by a chronic, relapsing inflammatory response. Elevation of several cytokines, with important immunoregulatory and proinflammatory activities have been demonstrated during active inflammatory bowel disease (IBD). These cytokines, including interleukin-1 (IL-1), IL-6, IL-8 and GM-CSF, may play an important role in the initiation and amplification of the inflammatory response leading to intestinal injury. There is increasing evidence that IL-1 is activated early in the cascade of events leading to inflammation. Therefore, IL-1 has been implicated as a primary target for therapeutic intervention for the treatment of several inflammatory diseases, including IBD. In addition, a mucosal imbalance of intestinal IL-1 and IL-1ra is present in patients with IBD, suggesting that insufficient production of endogenous IL-1ra may contribute to the pathogenesis of chronic gut inflammation. Preliminary studies examining the association between newly described polymorphisms in the IL-1 gene cluster and IBD have provided new insight into the genetic predisposition to UC. This article will review current progress in understanding the role of Il-1 and Il-1ra in IBD, as well as discuss recently described polymorphisms in the Il-1 gene cluster and their association with UC and CD.
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PMID:Interleukin-1 and interleukin-1 receptor antagonist in inflammatory bowel disease. 889 1

Glucocorticoids inhibit the expression and action of most cytokines. This is part of the in vivo feed-back system between inflammation-derived cytokines and CNS-adrenal produced corticosteroids with the probable physiological relevance to balance parts of the host defence and anti-inflammatory systems of the body. Glucocorticoids modulate cytokine expression by a combination of genomic mechanisms. The activated glucocorticoid-receptor complex can (i) bind to and inactivate key proinflammatory transcription factors (e.g. AP-1, NF kappa B). This takes place at the promotor responsive elements of these factors, but has also been reported without the presence of DNA; (ii) via glucocorticoid responsive elements (GRE), upregulate the expression of cytokine inhibitory proteins, e.g. I kappa B, which inactivates the transcription factor NF kappa B and thereby the secondary expression of a series of cytokines; (iii) reduce the half-life time and utility of cytokine mRNAs. In studies with triggered human blood mononuclear cells in culture, glucocorticoids strongly diminish the production of the 'initial phase' cytokines IL-1 beta and TNF-alpha and the 'immunomodulatory' cytokines IL-2, IL-3, IL-4, IL-5, IL-10, IL-12 and IFN-gamma, as well as of IL-6, IL-8 and the growth factor GM-CSF. While steroid treatment broadly attenuates cytokine production, it cannot modulate it selectively, e.g. just the TH0, the TH1 or the TH2 pathways. The production of the 'anti-inflammatory' IL-10 is also inhibited. The exceptions of steroid down-regulatory activity on cytokine expression seem to affect 'repair phase' cytokines like TGF-beta and PDGF. These are even reported to be upregulated, which may explain the rather weak steroid dampening action on healing and fibrotic processes. Some growth factors, e.g. G-CSF and M-CSF, are only weakly affected. In addition to diminishing the production of a cytokine, steroids can also often inhibit its subsequent actions. Because cytokines work in cascades, this means that steroid treatment can block expression of the subsequent cytokines. The blocked cytokine activity does not depend on a reduced cytokine receptor expression; in fact available in vitro investigations show that while the cytokine expression is blunted, its receptor is upregulated. The cellular studies presented here may represent the maximum potential of steroids to modulate cytokine expression in human mononuclear cells. It remains to be determined by clinical-experimental studies how effective cytokine modulation can be achieved in situ in inflamed bowel by systemic or by topical steroid therapy. Such studies may also answer whether a blocked cytokine production/action is the key or just a secondary mechanism behind the unique efficacy of steroids in active inflammatory bowel disease.
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PMID:Cytokine modulation by glucocorticoids: mechanisms and actions in cellular studies. 889 6

The presence of auto-antibodies and hypergammaglobulinaemia in patients with primary sclerosing cholangitis (PSC) suggest an overactive humoral immune system. Serum cytokines, measured using in-house double monoclonal sandwich ELISA, were used to assess the state of cellular and humoral immunity in this condition by comparison with sex and age matched normal controls and patients with alcoholic cirrhosis (AC). Soluble CD23 (sCD23) as a marker of humoral immunity was significantly elevated in PSC (N = 31) relative to patients with AC (N = 12) and the control group (N = 20) (P < 0.0001 and P < 0.001 respectively). Serum interleukin (IL) 10, as an anti-inflammatory cytokine and IL8, as a marker of neutrophil activation were significantly elevated in patients with PSC relative to those with AC and the controls (P < 0.001 and P < 0.05 respectively). Interferon gamma, as a marker of cellular immunity, and granulocyte-macrophage colony stimulating factor, a marker of monocyte/macrophage function were similar in all the groups. Cytokines and sCD23 were no different between patients with AC and the control group. While more than two thirds of the patients with PSC were positive for ANCA, there was no correlation between the presence of ANCA or ANCA titre and serum levels of either IL8, IL10 and sCD23. These results suggest exaggerated humoral immunity in PSC. The raised levels of IL10 and IL8 in PSC are discussed in the context of inflammatory bowel disease and liver dysfunction.
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PMID:Serum levels of interleukins 8 and 10, interferon gamma, granulocyte-macrophage colony stimulating factor and soluble CD23 in patients with primary sclerosing cholangitis. 954 83

Recombinant human interleukin 10 (rhuIL-10) inhibits the production of proinflammatory cytokines and has shown promise in the treatment of inflammatory bowel disease. Clinical trials have been accompanied by a reversible decline in platelet counts. We conducted a randomized, double-blinded, placebo-controlled, parallel group trial in 12 healthy volunteers to investigate the aetiology of rhuIL-10-induced thrombocytopenia. Eight volunteers received 8 microg/kg/d of rhuIL-10 subcutaneously, while four subjects received a placebo alone for 10 d. A reversible decline in the platelet counts from a mean of 275 x 10(9)/l to 164 x 10(9)/l was observed in the IL-10-treated cohort (P = 0.012). A fall in the haemoglobin mean levels was also observed in the IL-10-treated cohort from 13.7 to 11.7 g/dl (P = 0.011). No significant change was observed in the bone marrow cellularity or myeloid/erythroid ratio or in the number of megakaryocytes per high-powered field (HPF). A fall was observed in the number of megakaryocyte colony-forming units (CFU-MKs) after the administration of IL-10 compared with those receiving the placebo (P = 0.068). No difference in the change in granulocyte-macrophage CFUs (CFU-GMs), mixed lineage CFUs (CFU-GEMMs) or erythroid burst-forming units (BFU-Es) was observed when comparing the IL-10- vs. placebo-treated groups (P > 0.465). Serum cytokine levels of thrombopoietin (TPO). IL-6 and granulocyte-macrophage colony stimulating factor (GM-CSF) were not decreased following IL-10 administration. In fact, both TPO and GM-CSF appeared to be slightly increased in the serum. All subjects underwent In111-labelled platelet survival studies with liver/spleen scans to assess splenic sequestration prior to and then on day 7 of treatment. A significant reduction in splenic sequestration of platelets (P =0.012) was observed in the IL-10-treated group, but not in the placebo-treated subjects.
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PMID:Interleukin 10-induced thrombocytopenia in normal healthy adult volunteers: evidence for decreased platelet production. 1109 Nov 88

Chronic inflammatory bowel disease (IBD)-like colitis is occasionally associated with glycogen storage disease-type 1b (GSD-1b). We describe a 17-year old boy with GSD-1b who developed an IBD-like colitis. Roentgenography and colonoscopy showed the lead-pipe appearance of the colon and circumferential ulcers. Histopathologic examination revealed nonspecific inflammation without granulomatous lesions. High-dose granulocyte-colony stimulating factor (G-CSF) and sulfasalazine led to the resolution of the colitis, although neutropenia continued. Besides this case, 10 published cases of GSD-1b and IBD-like colitis were reviewed. All cases had severe neutropenia and/or neutrophil dysfunction. The mean onset of bowel disease was 12.3 years of age. Seven cases required surgical treatment. All five patients with G-CSF/GM-CSF therapy showed clinical remission. These findings suggest that IBD-like colitis is a grave complication of GSD-1b and that recurrent enteric infections due to neutrophil deficiency may contribute to the development of this bowel disease.
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PMID:Inflammatory bowel disease-like colitis in glycogen storage disease type 1b. 1138 85

Our understanding of the etiology and pathogenesis of IBD has improved extensively over the past years. At the center of the pathogenesis seems to be an excessive pro-inflammatory immune reaction towards normal intestinal flora. The different factors involved in this concept will form the focus of this review. The initial phase of antigen processing and presentation can be influenced by either modulation of the intestinal flora via antibiotics or probiotics or by direct stimulation of macrophages through GM-CSF treatment. Antigen recognition and activation of T-cells can be down-regulated by immunosuppressives such as azathioprine, CsA or methotrexate thus building the basis for current treatment in IBD. The pro-inflammatory character of the immune reaction is defined by the predominance of certain T-cell subpopulations. By targeting cytokines the disbalance of these subpopulation should be reconstituted. Here we will focus first on preliminary clinical as well as experimental data for the pro-inflammatory mediators IL-12 and IL-18 as well as for the anti-inflammatory cytokine IL-10. Second, the clinical data for the TNFalpha antibody that has been proven to be efficacious in Crohn's disease and the associated risks will be discussed. Last, recent clinical and experimental data on targeting cell adhesion as well as intracellular signaling pathways will be presented. In summary, with regard to this review, treatments, which intervene as early as possible in the initiation of the pathological immune reaction and simultaneously have a favorable side-effect profile, must be the focus of future research.
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PMID:Therapeutic approaches in inflammatory bowel disease based on the immunopathogenesis. 1563 10

NOD1 is an intracellular pattern-recognition receptor specific for Gram-negative peptidoglycan that is important in host response to infections (e.g. Helicobacter pylori and Shigella flexneri). Genetic variation in NOD1 predisposes to asthma and inflammatory bowel disease. Functional responses have not previously been studied in primary human cells. NOD1 activation by low nanomolar concentrations of the specific muropeptide ligand M-TriDAP induced minimal human peripheral blood mononuclear cell TNF-alpha, IL-1beta or IL-10 secretion, but synergistically increased Toll-like receptor (TLR)-induced responses. Synergistic responses were seen across multiple ligands (to TLR1/2, 2/6, 4, 5, 7/8) and a broad range of cytokine secretion (TNF-alpha, IL-1alpha, IL-1beta, IL-4, IL-6, IL-10, GM-CSF). Synergy was also observed in the allogeneic mixed lymphocyte reaction. These responses were similar in cells homozygous for Crohn's disease-associated NOD2 mutations. In contrast to cell lines, primary human peripheral blood mononuclear cells respond to NOD1 muropeptides at approximately 100-fold lower concentrations. Cross-talk between cytosolic NOD1 and membrane-bound TLR enhances responses to the multiple antigens simultaneously presented by a microbe.
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PMID:Synergistic enhancement of Toll-like receptor responses by NOD1 activation. 1602 3

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

On the basis of several studies that have been completed to date, some growth factors appear promising for the treatment of inflammatory bowel disease: keratinocyte-like growth factor-2 (KGF-2), epidermal growth factor (EGF) enemas used in combination with oral mesalamine, somatropin (human growth hormone), and sargramostim (recombinant human GM-CSF). The results of these studies are highlighted and suggest that new insights into the regulation of intestinal immunity may provide effective synergistic or single-agent treatment alternatives to immunosuppression for inflammatory bowel disease. These data focus on the reparative components of mucosal homeostasis.
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PMID:Growth factors as treatment options for intestinal inflammation. 1705 9


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