Consequence of functional Nod2 and Tlr4 mutations on gene transcription in Crohn's disease patients.

The concept that mutations in germ-line encoded pattern recognition receptors with immune activating functions are associated with an increased incidence in Crohn's disease (CD) is gaining acceptance. Whether these mutations have similar or distinct effects on cellular physiology remains obscure. The incidence of three single nucleotide polymorphisms (SNPs) within the Nod2 gene and one functional SNP within both the Tlr4 and Tlr5 gene in a Dutch cohort of 637 patients with inflammatory bowel disease and 127 controls was investigated.

Rapid immunosuppressive effects of glucocorticoids mediated through Lck and Fyn.

Glucocorticoids (GCs) are effective immunosuppressive agents and mediate well-defined transcriptional effects via GC receptors. There is increasing evidence that GCs also initiate rapid nongenomic signaling events. Using activated human CD4(+) lymphocytes and a peptide array containing 1176 different kinase consensus substrates, we generated a comprehensive profile of GC-induced rapid effects on signal transduction.

Infliximab induced T lymphocyte apoptosis in Crohn's disease.

Crohn's disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract of unknown origin. Therapies include immune modulating agents, biological therapies, and surgery. The activity and efficacy of the anti-tumor necrosis factor (TNF) therapies infliximab and etanercept have proved to be different: infliximab is effective to induce and maintain remission in refractory CD, while etanercept is not.

Targeting tumor necrosis factor-alpha in inflammatory bowel disease: why, how, and when?

A large proportion of patients with inflammatory bowel disease require more effective therapy, especially for the prevention of disease relapse. Recent therapeutic advances have focused on biologicals (monoclonal antibodies, therapeutic peptides, antisense oligonucleotides) that aim to neutralize specific proinflammatory proteins. This has proved successful for the anti-TNF-alpha antibody infliximab in patients with Crohn disease, but recent studies failed to demonstrate the efficacy of different anti-TNF-alpha strategies.

New cytokine therapeutics for inflammatory bowel disease.

Conventional therapy for inflammatory bowel diseases rely on corticosteroids and 5-aminosalicylates combined with immunosuppressive agents for maintenance. These drugs are not always effective and may inflict serious side effects. Other therapies are therefore awaited.

Lactobacillus rhamnosus induces peripheral hyporesponsiveness in stimulated CD4+ T cells via modulation of dendritic cell function.

Background: Although it is widely recognized that the intake of so-called probiotic microorganisms is beneficial in chronic mucosal inflammation and topical allergic disease, the immunologic details explaining how such bacteria can exert these effects remain obscure.

Objective: We determined whether Lactobacillus rhamnosus can modulate T cell responses in vitro and in vivo.

Design: In vitro, human monocyte-derived dendritic cells (DCs) matured in the presence of L.

Kinome profiling for studying lipopolysaccharide signal transduction in human peripheral blood mononuclear cells.

The DNA array technique allows comprehensive analysis of the genome and transcriptome, but the high throughput array-based assessment of intracellular signal transduction remains troublesome. The goal of this study was to test a new peptide array technology for studying the activity of all kinases of whole cell lysates, the kinome. Cell lysates from human peripheral blood mononuclear cells before and after stimulation with lipopolysaccharide were used for in vitro phosphorylation with [gamma-33P]ATP arrays consisting of 192 peptides (substrates for kinases) spotted on glass.

The pathogenicity of cytomegalovirus in inflammatory bowel disease: a systematic review and evidence-based recommendations for future research.

During recent years, a clear association between complicated courses of ulcerative colitis and the presence of cytomegalovirus (CMV) has been established. The exact pathogenic role of CMV in these patients remains unclear despite a great number of published reports. Therefore, we undertook a systematic review to appraise critically all available evidence in the literature on the role of CMV during inflammatory bowel disease.

Endoscopy in inflammatory bowel diseases.

A correct diagnosis, adequate assessment of disease activity, avoidance of surgery by endoscopic interventions, and effective cancer surveillance make endoscopy crucial in the management of inflammatory bowel diseases (IBDs). Impressive technical developments of several endoscopic techniques over the past few decades have allowed a detailed visual impression of the affected gut and enable tissue sampling and various therapeutic interventions. Here we propose guidelines for endoscopy in inflammatory bowel disease, and review all currently available endoscopic techniques relevant to the proper treatment of IBD patients.

Pharmacokinetics of 6-mercaptopurine in patients with inflammatory bowel disease: implications for therapy.

Proper prospective pharmacokinetic studies of 6-mercaptopurine (6-MP) in inflammatory bowel disease (IBD) patients are lacking. As a result, conflicting recommendations have been made for metabolite monitoring in routine practice. The authors have evaluated 6-MP pharmacokinetics in IBD patients, including the genetic background for thiopurine methyltransferase (TPMT).

Interleukin-10-based therapy for inflammatory bowel disease.

In recent years it has become clear that chronic inflammatory bowel disease (IBD), especially Crohn's disease (CD), is caused by a loss of tolerance against the autologous bacterial flora of the intestine. Tolerance against the indigenous flora requires optimal recognition of antigens by pattern recognition receptors and the presence of important regulatory cells and cytokines. Interleukin-10 (IL-10) has a major role in the regulatory network of cytokines controlling mucosal tolerance, and it is, therefore, not surprising that this cytokine is proposed as a potent anti-inflammatory biological therapy in chronic IBD.

Infliximab therapy in Crohn's disease: safety issues.

Infliximab has become a valuable addition to the therapeutic arsenal for Crohn's disease. Although the rate of adverse events was relatively low in the premarketing trials, several investigators have recently reported experience in large groups of patients. This has shed more light on safety aspects of infliximab therapy, which should change the approach towards patients prior to infliximab infusion.

Infliximab but not etanercept induces apoptosis in lamina propria T-lymphocytes from patients with Crohn's disease.

Background & Aims: Steroid-refractory Crohn's disease responds to therapy with the chimeric anti-tumor necrosis factor (TNF)-alpha antibody infliximab. Etanercept, a recombinant TNF receptor/immunoglobulin G fusion protein, is highly effective in rheumatoid arthritis but not in Crohn's disease. Because both infliximab and etanercept are TNF-alpha-neutralizing drugs, we investigated the differences in TNF-alpha-neutralizing capacity and human lymphocyte binding and apoptosis-inducing capacity of both molecules.

Increased expression of DC-SIGN+IL-12+IL-18+ and CD83+IL-12-IL-18- dendritic cell populations in the colonic mucosa of patients with Crohn's disease.

Dentritic cells (DC) as antigen-presenting cells are most likely responsible for regulation of abnormal T cell activation in Crohn's disease (CD), a chronic inflammatory bowel disease. We have analyzed the expression of activation and maturation markers on DC in the colon mucosa from patients with CD compared with normal colon, using immunohistochemical techniques. We found two distinct populations of DC present in CD patients: a DC-specific ICAM-3 grabbing non-integrin (DC-SIGN)(+) population that was present scattered throughout the mucosa, and a CD83(+) population that was present in aggregated lymphoid nodules and as single cells in the lamina propria.

Mitogen activated protein (MAP) kinase signal transduction pathways and novel anti-inflammatory targets.

Over the last decade important advances have been made in our understanding of the molecular events underlying cellular responses to extracellular signals. Increased understanding of signal transduction mechanisms and gene regulation involved in immune responses has created opportunities for the discovery of novel therapeutic compounds useful in treating inflammatory disorders. One of the best studied signalling routes is the mitogen activated protein (MAP) kinase signal transduction pathway which plays a crucial role in many aspects of immune mediated inflammatory responses.

Infliximab treatment for Crohn's disease: one-year experience in a Dutch academic hospital.

The aim of this study was to report the 1-year clinical experience with infliximab treatment for Crohn's disease (CD) in the Netherlands. All 73 CD patients receiving infliximab infusions were prospectively followed during 1 year after the drugs' registration in the Netherlands. Clinical response and adverse events were assessed for both active luminal disease as well as fistulous disease.

Inhibition of stress-activated MAP kinases induces clinical improvement in moderate to severe Crohn's disease.

Background & Aims: We investigated if inhibition of mitogen-activated protein kinases (MAPKs) was beneficial in Crohn's disease.

Methods: Inhibition of JNK and p38 MAPK activation with CNI-1493, a guanylhydrazone, was tested in vitro. Twelve patients with severe Crohn's disease (mean baseline, CDAI 380) were randomly assigned to receive either 8 or 25 mg/m(2) CNI-1493 daily for 12 days.

Anti- and proinflammatory cytokines in the pathogenesis of tissue damage in Crohn's disease.

Crohn's disease is a chronic inflammatory bowel disease of unknown origin. The understanding of the pathogenesis of inflammatory bowel diseases has been greatly advanced by manipulations of the immune system in mice using targeted disruptions of genes that encode specific anti- and proinflammatory cytokines, as well as T-cell subsets. The outcome of these experiments has implicated CD4+ lymphocytes and certain proinflammatory cytokines (tumour necrosis factor-alpha, interleukin-12) as playing a central role in the pathogenesis of mucosal inflammation in Crohn's disease.

Beneficial effect of treatment with a monoclonal anti-tumor necrosis factor-alpha antibody on markers of coagulation and fibrinolysis in patients with active Crohn's disease.

Crohn's disease has frequently been associated with coagulation abnormalities, causing intravascular deposition of fibrin and local infarction which can subsequently compromise the gut mucosa. Also, arterial and venous thromboembolic complications of larger vessels appear to be associated with Crohn's disease. Coagulation activation in patients with Crohn's disease could be a result of increased serum and tissue levels of cytokines, as reported.

Efficacy of recombinant granulocyte colony-stimulating factor (rhG-CSF) in experimental colitis.

Inflammatory bowel disease is associated with mucosal neutrophil recruitment and activatation, mediated in part by arachidonic acid metabolites. G-CSF attenuates the immune response to sepsis and ameliorates glycogen storage disease Ib-related colitis. These actions may be effected through the shedding of neutrophil adhesion molecules, or inhibition of proinflammatory mediator synthesis.

Attenuation of the inflammatory response in an animal colitis model by neutrophil inhibitory factor, a novel beta 2-integrin antagonist.

Background: Neutrophils are significant effector cells in acute inflammatory bowel disease. Recruitment of these cells is dependent on beta 2-integrin-mediated adhesion and transmigration. The efficacy of neutrophil inhibitory factor (NIF), an antagonist of the beta 2-integrin CD11b/CD18, in ameliorating inflammation was tested in an animal model of acute colitis.

Lexipafant (BB-882), a platelet activating factor receptor antagonist, ameliorates mucosal inflammation in an animal model of colitis.

Objective: To assess the anti-inflammatory action of lexipafant (BB-882), a platelet activating factor antagonist, in an animal model of acute colitis.

Design: An animal intervention study.

Methods: Following the rectal instillation of formalin 0.