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Daniel W Hommes

Publications and source records attributed to Daniel W Hommes.

14 recordsLinked to original sources
PubMed2007

Comparative analysis of colonic gene expression of three experimental colitis models mimicking inflammatory bowel disease.

BACKGROUND: Mouse models of inflammatory bowel diseases (IBD) are used to unravel the pathophysiology of IBD and to study new treatment modalities, but their relationship to Crohn's disease (CD) or ulcerative colitis (UC) is speculative. METHODS: Using Agilent mouse TOX oligonucleotide microarrays, we analyzed colonic gene expression profiles in three widely used models of experimental colitis. In 2 of the models (TNBS and DSS-induced colitis), exogenous agents induce the colitis. In the third model the colitis is induced after transfer of a T-cell population (CD4(+)CD45RB(high) T cells) that lacks regulatory cells into an immunodeficient host. RESULTS: Compared with control mice, in DSS, TNBS, and the CD45RB transfer colitis mice, 387, 21, and 582 genes were more than 2-fold upregulated in the intestinal mucosa. Analyses of exclusively shared gene expression profiles between the different models revealed that DSS/transfer colitis share 69 concordantly upregulated genes, DSS/TNBS 6, and TNBS/transfer colitis 1. Seven genes were upregulated in all three models. The CD45RB transfer model expression profile included the most genes that are known to be upregulated in IBD. Of 32 genes that are known to change transcriptional activity in IBD (TNF, IFN-gamma, Ltbeta, IL-6, IL-16, IL-18R1, IL-22, CCR2, 7, CCL2, 3, 4, 5, 7, 11, 17, 20, CXCR3, CXCL1, 5, 10, Mmp3, 7,9, 14, Timp1, Reg3gamma, and Pap, S-100a8, S-100a9, Abcb1, and Ptgs2), 2/32 are upregulated in TNBS, 15/32 are upregulated or downregulated in DSS and 30/32 are upregulated or downregulated in the CD45RB transfer colitis. CONCLUSION: The pattern of gene expression in the CD45RB transfer model most closely reflects altered gene expression in IBD.

Animals↗
PubMed2006

Glucocorticoids cause rapid dissociation of a T-cell-receptor-associated protein complex containing LCK and FYN.

Although glucocorticoid (GC)-induced nongenomic effects have been reported, the underlying mechanisms remain unexplained. We previously described that lymphocyte-specific protein tyrosine kinase (LCK) and FYN oncogene related to SRC, FGR, YES (FYN) mediate GC-induced inhibition of T-cell-receptor (TCR) signalling. Here we characterize the underlying molecular mechanism. The present study shows that the GC receptor is part of a TCR-linked multiprotein complex containing heat-shock protein (HSP)90, LCK and FYN, which is essential for TCR-dependent LCK/FYN activation. Experiments with cells transfected with GC-receptor short interfering RNA (siRNA) showed that the GC receptor is an essential component of the TCR signalling complex. Short-term GC treatment induces dissociation of this protein complex, resulting in impaired TCR signalling as a consequence of abrogated LCK/FYN activation. HSP90siRNA-transfected cells are not able to assemble this TCR-associated multiprotein complex, and accordingly HSP90siRNA treatment mimics GC effects on LCK/FYN activities. These observations support a model for nongenomic GC-induced immunosuppression on the basis of dissolution of membrane-bound GC-receptor multiprotein complexes after GC-receptor ligation.

CD4 Antigens↗
PubMed2006

A phase I trial with transgenic bacteria expressing interleukin-10 in Crohn's disease.

BACKGROUND & AIMS: The use of living, genetically modified bacteria is an effective approach for topical delivery of immunomodulatory proteins. This strategy circumvents systemic side effects and allows long-term treatment of chronic diseases. However, treatment of patients with a living, genetically modified bacterium raises questions about the safety for human subjects per se and the biologic containment of the transgene. METHODS: We treated Crohn's disease patients with genetically modified Lactococcus lactis (LL-Thy12) in which the thymidylate synthase gene was replaced with a synthetic sequence encoding mature human interleukin-10. Ten patients were included in a placebo-uncontrolled trial. Patients were assessed daily for the presence of potential adverse effects by direct questioning and assessment of disease activity. We evaluated the presence and kinetics of LL-Thy12 release in the stool of patients by conventional culturing and quantitative polymerase chain reaction of LL-Thy12 gene sequences. RESULTS: Treatment with LL-Thy12 was safe because only minor adverse events were present, and a decrease in disease activity was observed. Moreover, fecally recovered LL-Thy12 bacteria were dependent on thymidine for growth and interleukin-10 production, indicating that the containment strategy was effective. CONCLUSIONS: Here we show that the use of genetically modified bacteria for mucosal delivery of proteins is a feasible strategy in human beings. This novel strategy avoids systemic side effects and is biologically contained; therefore it is suitable as maintenance treatment for chronic intestinal disease.

C-Reactive Protein↗
PubMed2006

Feasibility of evaluating Crohn's disease activity at 3.0 Tesla.

PURPOSE: To determine whether abdominal 3.0T MRI can be used for evaluation of Crohn's disease (CD) compared with ileocolonoscopy (CS), and to determine patient preference for MRI as opposed to CS. MATERIALS AND METHODS: Twenty patients scheduled for CS underwent MRI. At CS, disease severity was graded and the Crohn's Disease Endoscopic Index of Severity (CDEIS) was determined. Radiological grading (by two observers) was compared with endoscopic grading and CDEIS. Patient experience and preference were determined. RESULTS: In respectively 10 (observer 1) and 13 patients (observer 2) exact agreement between radiological and endoscopic grading was found. In respectively 10 and 7 patients radiological and endoscopic grading differed one level. No statistically significant correlation was found between radiological grading and CDEIS. Between bowel wall thickness and CDEIS weak to moderate correlations were found, and between bowel wall enhancement and CDEIS weak correlations were found. All patients preferred MRI over CS. CONCLUSION: It is feasible to perform abdominal 3.0T MRI using orally administered contrast medium for evaluation of CD, and this method can be considered a patient-friendly alternative to CS.

Adult↗
PubMed2006

Novel biological therapies for inflammatory bowel disease.

The success of biological therapy is best advocated by infliximab (IFX), which has dramatically improved medical therapy for Crohn's disease and now has been shown to be effective in the treatment of ulcerative colitis. Other anti-tumor necrosis factor (TNF) compounds have been tested in the treatment of Crohn's disease and will soon appear in the therapeutic armament. However, neutralization of TNF does not seem to be the most important mechanism of action of these therapies. Apoptosis of activated T cells was demonstrated after IFX treatment, and this may be the key to its success. Thus, other therapies that induce apoptosis in activated T cells, such as visilizumab, have a great chance to be of benefit. Biological therapies applied in inflammatory bowel disease appear to be safe, although therapy-related adverse events clearly have been recognized.

Journal Article↗
PubMed2006

Pharmacogenomics in inflammatory bowel disease.

Inherited variations in the nucleotide sequence of genes influence how individual patients respond to drugs. Most commonly, clinically significant genetic variations consist of single nucleotide polymorphisms (SNPs) within genes that affect drug disposition or drug targets. Up to now, relatively few clinically important examples of inherited traits that affect drug responses have been studied in detail. However, one of the well-characterized examples is highly relevant to inflammatory bowel disease therapeutics, that of thiopurine methyltransferase pharmacogenetics. Individuals with 2 normal alleles of the gene encoding thiopurine methyltransferase metabolize and clear thiopurines such as azathioprine and 6-mercaptopurine rapidly. Individuals with 1 normal and 1 variant allele are intermediate, whereas those with 2 variant alleles clear thiopurines very slowly. Intermediate and slow metabolizers are predisposed to have high active thiopurine drug levels and develop bone marrow suppression. Genomic era technology permits determination of large numbers of SNPs in large numbers of individuals. This capability is allowing the field of pharmacogenomics to become one of the most productive interfaces in translational biomedical research at present. By using high-throughput SNP genotyping, combined with careful phenotypic characterization of disease, pharmacogenomic research carries the potential of identifying individual biomarkers that predict the relative likelihood of benefit or risk from a therapeutic intervention. If this promise can be realized, pharmacogenomics will deliver the opportunity for personalized medicine.

Anti-Inflammatory Agents↗
PubMed2006

Intravenous pamidronate in combination with calcium and vitamin D: highly effective in the treatment of low bone mineral density in inflammatory bowel disease.

OBJECTIVE: Decreased bone mineral density (BMD) is common in inflammatory bowel disease (IBD) and an increased risk of fractures has been reported. Guidelines state bisphosphonate treatment for IBD patients with decreased BMD, but orally available bisphosphonates have been associated with gastrointestinal side effects and the absorption is poor. We investigated whether intravenous pamidronate is a safe and effective treatment. MATERIAL AND METHODS: Forty-nine IBD patients with decreased BMD as assessed by DEXA scan were treated with calcium 1000 mg and vitamin D 400 IU daily. In addition, 30 mg of pamidronate was administered intravenously every 3 months. DEXA scanning was performed prior to treatment, after 6 months and after 1 year. RESULTS: Of 49 IBD patients, 40 were osteoporotic and 9 were osteopenic. Twenty-six patients were female (mean age 40.8) and 23 were male (mean age 43.3). Treatment was discontinued in one patient because of fever after infusion. Otherwise, tolerability was excellent, and no adverse events were documented. A mean 0.51 increase of lumbar spine (L1-L4) T-scores was observed (CI 95% 0.35-0.67; p<0.0004). The effect of treatment on left femoral neck T-scores was less pronounced: 0.39 (CI 95% 0.24-0.53; p<0.0004). CONCLUSIONS: We conclude that intravenous pamidronate in combination with calcium and vitamin D is a well tolerated strategy for treating Crohn's disease associated osteopenia and osteoporosis. Although uncontrolled, treatment results in a significant increase of BMD in the lumbar spine.

Absorptiometry, Photon↗
PubMed2006

Pharmacokinetics of 6-thioguanine in patients with inflammatory bowel disease.

6-Thioguanine (6-TG) seems to be an attractive alternative in both AZA- and 6-MP-intolerant and -resistant IBD populations. However, little is known of 6-TG pharmacokinetics, metabolite levels, and their correlation with drug efficacy and toxicity in IBD patients. This study reports the 6-TG pharmacokinetics in a population of IBD patients and the predictive value of metabolite concentrations. Red blood cell (RBC) 6-thioguanine nucleotide (6-TGN) concentrations were measured in 28 IBD patients at t = 1, 2, 4, and 8 weeks after starting 6-TG, 20 mg once daily. Outcome measures included mean 6-TGN concentrations (+/-95% confidence interval [CI95%]) and their associations with TPMT genotype, 6-TG dose, and hematological, hepatic, pancreatic, and efficacy parameters during the 8 week period. Steady-state 6-TGN concentrations were reached after 4 weeks, indicating a half-life of approximately 5 days, and measured 856 (CI95% 715-997) pmol/8 x 10 RBCs. Large interpatient variability occurred at all time-points. No correlation was found between steady-state 6-TGN concentrations and drug dose per kilogram body weight. No significant differences in 6-TGN concentrations were found between patients with adverse events and patients without any event. Also, mean 6-TGN concentrations did not differ in patients with active disease versus patients in remission. In IBD patients on 6-TG treatment, large interindividual differences in metabolite concentrations occur. In our population, we could not demonstrate a clear relationship between 6-TGN concentrations on one hand and toxicity and efficacy on the other, as exist in AZA- and 6-MP-treated patients.

Adult↗
PubMed2006

Critical appraisal of the current practice in murine TNBS-induced colitis.

There is no standard practice in the induction of colitis by 2,4,6-trinitrobenzene sulfonic acid. In this review the current practice in 2,4,6-trinitrobenzene sulfonic acid colitis is studied using 20 recently published articles. We compare the different protocols, discuss the mechanism of disease and give recommendations for the future use of the model.

Animals↗
PubMed2005

Magnetic resonance imaging compared with ileocolonoscopy in evaluating disease severity in Crohn's disease.

BACKGROUND & AIMS: Abdominal magnetic resonance imaging (MRI) has shown promising results in the detection of Crohn's disease (CD)-related lesions. The purpose of this study was to assess the value of MRI in measuring disease activity in CD patients in comparison with ileocolonoscopy. METHODS: Thirty-one patients undergoing ileocolonoscopy because of suspicion of relapsing CD underwent MRI with water as intraluminal contrast medium. At endoscopy, disease severity was graded (4-point scale), and Crohn's Disease Endoscopic Index of Severity (CDEIS) was determined. Two radiologists independently interpreted the MRI scans. Radiologic grading (4-point scale) was compared with endoscopic grading of disease severity and CDEIS (overall, for all segments). Wall thickness and enhancement were compared with CDEIS. Patient experience and preference were determined. RESULTS: In, respectively, 14 and 14 patients (radiologist 1) and 16 and 11 patients (radiologist 2) an exact match or 1 level of difference in grading was scored with the endoscopist. Correlation between severity rated at MRI and CDEIS was moderate to strong with r = 0.61 (P < .001) for observer 1 and r = 0.63 (P < .001) for observer 2. Per segment, best correlation was seen in the terminal ileum (r = 0.63; P < .001, for both observers). Wall thickness correlated moderately to strongly with CDEIS (r = 0.57, P < .001 and r = 0.50, P < .001 for observers 1 and 2), whereas enhancement correlated weakly to moderately (r = 0.45, P < .001 and r = 0.42, P < .001). Patients experienced more pain during endoscopy, and all patients except 2 preferred MRI to endoscopy. CONCLUSION: MRI can correctly identify disease severity in patients with CD and is a patient-friendly alternative to ileocolonoscopy.

Adolescent↗
PubMed2004

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.

Catheterization↗
PubMed2004

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). Red blood cell (RBC) 6-thioguanine nucleotide (6-TGN) and 6-methylmercaptopurine ribonucleotide (6-MMPR) concentrations were measured in 30 IBD patients at 1, 2, 4, and 8 weeks after starting 6-MP, 50 mg once daily. Outcome measures included mean 6-TGN and 6-MMPR concentrations (+/- 95% confidence interval, CI95%) and their associations with TPMT genotype, 6-MP dose, and hematologic, hepatic, pancreatic, and efficacy parameters during the 8-week period. Steady-state concentrations were reached after 4 weeks, indicating a half-life of approximately 5 days for both 6-TGN and 6-MMPR; the concentrations were 368 (CI95% 284-452) and 2837 (CI95% 2101-3573) pmol/8 x 10 RBCs, respectively. Large interpatient variability occurred at all time points. TPMT genotype correlated with 6-TGN concentrations (0.576, P < 0.01), and patients with mutant alleles had a relative risk (RR) of 12.0 (CI95% 1.7-92.3) of developing leukopenia. A 6-MMPR/6-TGN ratio less than 11 was associated with therapeutic efficacy. Based on this pharmacokinetic analysis, therapeutic drug monitoring is essential for rational 6-MP dosing.

Adult↗
PubMed2004

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. We identified and analyzed more than 30 case reports and 9 case series. Based on these results, we propose a model for viral replication during inflammation and provide recommendations for future research.

Colitis, Ulcerative↗