The demonstration that oral immunization with lysates of Helicobacter or with Helicobacter pylori urease can protect mice against H. felis infection opened the field of vaccine development against Helicobacter infections. More recently,... more
The demonstration that oral immunization with lysates of Helicobacter or with Helicobacter pylori urease can protect mice against H. felis infection opened the field of vaccine development against Helicobacter infections. More recently, the same antigen preparations were used successfully as a therapeutic vaccine able to cure the infection, and additional protective antigens were identified. Evidence from animal studies suggests that protection is medicated by mucosal antibodies, in association with a T helper type 2 cell cellular immune response. Vaccine adjuvants, delivery systems, and therapeutic vaccination are likely to be the areas of major progress in the future.
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Infliximab is a monoclonal chimeric antibody, with high affinity and specificity for tumour necrosis factor alpha (TNFalpha) that plays a central role in the pathogenesis of immune mediated inflammatory disorders including Crohn's... more
Infliximab is a monoclonal chimeric antibody, with high affinity and specificity for tumour necrosis factor alpha (TNFalpha) that plays a central role in the pathogenesis of immune mediated inflammatory disorders including Crohn's disease and ulcerative colitis. Globally over 600000 patients have been treated with infliximab to date. This global experience led to a better definition of the overall safety and efficacy profile of this medication. The goal of the present recommendations is to provide practical information to physicians involved in the care of patients with inflammatory bowel disease.
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Indigo carmine (IC) dye staining has previously been reported to increase the detection rate of diminutive flat neoplastic lesions which show a high rate of severe dysplasie. Oral ingestion of an IC capsule with a polyethylene glycol... more
Indigo carmine (IC) dye staining has previously been reported to increase the detection rate of diminutive flat neoplastic lesions which show a high rate of severe dysplasie. Oral ingestion of an IC capsule with a polyethylene glycol electrolyte lavage solution (PEG-ELS) was shown to be an effective chromescopy technique in combination with magnifying colenoseopy. Our aim was to study the utility of this technique at the same dose of IC previously used in routine nonmagnifying colonosco W and to assess iftbe quality of colenosenpy was improved with IC chromosco W Methods: 100 consecutive colonoscopies were performed in 100 unselected outpatients (45 F, 55M) with a mean age of 56.6 (20-82 yr), who gave written infunned consenL Patients ingasWd an IC capsule containing 100 mg dye powder during prepargien for colunoscopy at randomized timepoints: either before (A; n=I0) the PEG-ELS, after ingestion of the first liter (EL; nffi2g), second liter (C; n=32) or at the and of the lavnge (D; nffi30). Colonoscopies were performed with an Olympus video-colunoscopa CF-100HI or C F- 1301. Endescopists (nffi4) were asked to assess the shape, size and site of the lesions and to differentiale between flat, pedanculated or sessile polyps. Contrast resulting from the IC dye was judged as excellenL good, fair or weak. The endoscopist had to assess if colonuscopy was improved by IC stain or not. Results: The administration of IC capsules was well tolerated by all patients, no side effects occurred. In 20% of patients results of IC staining were considered fair to excellent, in 80% weak or insufficient. Contrast obtained was insufficient in group A (100% weak) but was similarly weak in groups B (75%), C (75%) and D (83%). Only 8% of cofonosenpies were jndged to have been improved by oral IC staining. Decreased visibility due to coloration of liquid stools was the main disadvantage of IC staining. Flat lesions were detected in 11 nut 0f44 patients presenting with single up to multiple polyps or polypoid lesions. Histology revealed normal sigmoid mucosa in 2/11 patients, hyperplastic polyps in 8111 and an adenomatous polyp with low-grade dysplasia in 1/11 patients. Conclusions: IC staining with orally ingested capsules often results in an insufficient contrast in colonic mueosa independently of the time the capsule is administered. In uuseleeted patients orally administered IC does not fecilitato routine celonoseopy and does not seem to inar, sse the detection rate of flat lesions when using non-mngnifying video-celonoscopes
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Gastroenterology, Volume 120, Issue 5, Pages A708, April 2001, Authors:Gian Oh Dorta; David Antos; Joergen Radke; Stefan Miehlke; Jan Martinek; Irene Corthesy-Theulaz; Andre Blum; Pierre Michetti; Patrick Isler; Manfred Stolte; Dirk... more
Gastroenterology, Volume 120, Issue 5, Pages A708, April 2001, Authors:Gian Oh Dorta; David Antos; Joergen Radke; Stefan Miehlke; Jan Martinek; Irene Corthesy-Theulaz; Andre Blum; Pierre Michetti; Patrick Isler; Manfred Stolte; Dirk Claeys; Ekkehard Bayerdoerffer. ...
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Research Interests: Immune response, Gastroenterology, Biology, Helicobacter pylori, Medicine, and 15 moreHumans, Bacterial Toxins, Escherichia coli, Enterotoxins, Female, Male, Immunization, Epidemiology of Helicobacter pylori infection, Clinical Sciences, Middle Aged, Adult, Immunogenicity, H Pylori, Breath Test, and Immunoglobulin A
Background: Controlled clinical trials have demonstrated the efficacy and safety of adalimumab in patients with moderate-to-severe Crohn’s disease (CD), but there is, however, only limited long-term experience with adalimumab in daily... more
Background: Controlled clinical trials have demonstrated the efficacy and safety of adalimumab in patients with moderate-to-severe Crohn’s disease (CD), but there is, however, only limited long-term experience with adalimumab in daily practice. Aim: To assess the long-term effectiveness and safety of adalimumab in a multicenter cohort of practice-based patients with moderate-to-severe CD. Methods: We retrospectively reviewed the charts of CD patients who received adalimumab over a 3-year period. Disease severity was scored using the Harvey-Bradshaw index (HBI). Remission was defined as an HBI of ≤4 and response as a reduction in the HBI of >3 points at evaluation compared to the baseline. Univariate logistic regression analysis was used to identify the predictive variables associated with response. Results: The charts of 55 patients were reviewed; remission and response rates observed at weeks 4–6 were 52.7 and 83.6%, respectively. Remission was maintained at weeks 12, 24 and 52 ...
Research Interests: Medicine, Humans, Female, Disease, Digestion, and 15 moreMale, Cohort Study, Disease Severity, Monoclonal Antibodies, Cohort, Logistic Regression Analysis, Clinical Sciences, Adult, Controlled Clinical Trial, Indexation, Long Term Effect, Logistic Models, Crohn Disease, Multicenter Study, and Adalimumab
We have developed a 14C-urea breath test to follow the course of Helicobacter felis infection in mice. Peak 14CO2 production occurred approximately 8 min after substrate administration. The test values were compared to those from a rapid... more
We have developed a 14C-urea breath test to follow the course of Helicobacter felis infection in mice. Peak 14CO2 production occurred approximately 8 min after substrate administration. The test values were compared to those from a rapid urease test and correlated with the presence of pathogens by histology. The sensitivity was 99%, specificity 91%, positive predictive value 95% and negative predictive value 99% when the assay was conducted in fasted mice. We conclude that in mice the breath test analysis is a useful noninvasive method for detecting the presence of H. felis or for evaluating therapeutic agents affecting growth or survival of the organism.
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Novel strategies are needed to control infection with Helicobacter pylori. Prophylactic and therapeutic immunization against this gastric pathogen is possible in animal models, and initial human studies in H. pylori-infected subjects... more
Novel strategies are needed to control infection with Helicobacter pylori. Prophylactic and therapeutic immunization against this gastric pathogen is possible in animal models, and initial human studies in H. pylori-infected subjects showed that immunization with H. pylori urease is both safe and immunogenic. In rodents, gastric protection against Helicobacter species infection does not depend on the humoral immune response, and a prominent role of the major histocompatibility complex II-restricted CD4(+) T-cell response is recognized; however, much remains to be learned about the mechanisms of effective bactericidal response. A clear understanding of the basic mechanisms of gastric immune protection in humans is of the utmost importance for the development of an effective human vaccine. More potent vaccines are likely to be required to induce protection in humans. The availability of two complete genome sequences of H. pylori represents a unique opportunity to identify novel vaccine antigens. Multivalent vaccines delivered by recombinant attenuated bacteria or administered with nontoxic adjuvants need to be evaluated in relevant models.
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Summary Macrophages play a critical role in intestinal wound repair. However, the mechanisms of macrophage-assisted wound repair remain poorly understood. We aimed to characterize more clearly the repair activities of murine and human... more
Summary Macrophages play a critical role in intestinal wound repair. However, the mechanisms of macrophage-assisted wound repair remain poorly understood. We aimed to characterize more clearly the repair activities of murine and human macrophages. Murine macrophages were differentiated from bone marrow cells and human macrophages from monocytes isolated from peripheral blood mononuclear cells of healthy donors (HD) or Crohn's disease (CD) patients or isolated from the intestinal mucosa of HD. In-vitro models were used to study the repair activities of macrophages. We found that murine and human macrophages were both able to promote epithelial repair in vitro. This function was mainly cell contact-independent and relied upon the production of soluble factors such as the hepatocyte growth factor (HGF). Indeed, HGF-silenced macrophages were less capable of promoting epithelial repair than control macrophages. Remarkably, macrophages from CD patients produced less HGF than their HD ...
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MDCK cells expressing the polymeric immunoglobulin (poly-Ig) receptor, cocultured with IgA-producing hybridoma cells, transported dimeric IgA (dIgA) from the basolateral into the lumenal compartment, where it was recovered as secretory... more
MDCK cells expressing the polymeric immunoglobulin (poly-Ig) receptor, cocultured with IgA-producing hybridoma cells, transported dimeric IgA (dIgA) from the basolateral into the lumenal compartment, where it was recovered as secretory component-dIgA complexes. The tail of the receptor was phosphorylated on serines 664 and 726. Each serine was mutated to alanine. Appearance of A726 receptor at the basolateral surface was reduced approximately 5-fold. This was accompanied by a approximately 5-fold reduction in dIgA transcytosis. Basolateral delivery of receptor was not affected by mutation A664, and in the absence of dIgA, the receptor accumulated in recycling basolateral endosomes. In coculture, however, dIgA transcytosis by A664 receptor was normal. Thus, entry of receptor into the transcytotic pathway requires Ser-664 phosphorylation only in the absence of dIgA.
Research Interests: Molecular Biology, Biology, Cell Biology, Medicine, Biological Sciences, and 15 moreDogs, Kidney, Mutation, Animals, Cell, Plant tissue Culture Techniques, Cell Polarity, Phosphorylation, Epithelium, Amino Acid Sequence, Base Sequence, Hybridomas, Molecular Sequence Data, Immunoglobulin A, and Medical and Health Sciences
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Research Interests: Immunology, Biology, Autoimmunity, Medicine, Signal Transduction, and 15 moreCell Differentiation, Humans, Mutation, Mice, Primary Immunodeficiency, Female, Animals, Clinical, Male, Homeostasis, Clinical Investigation, Adoptive Transfer, Regulatory T cell, Medical and Health Sciences, and In Vitro Techniques
Secretory immunoglobulin A (IgA) antibodies (sIgA) directed against cholera toxin (CT) and surface components of Vibrio cholerae are associated with protection against cholera, but the relative importance of specific sIgAs in protection... more
Secretory immunoglobulin A (IgA) antibodies (sIgA) directed against cholera toxin (CT) and surface components of Vibrio cholerae are associated with protection against cholera, but the relative importance of specific sIgAs in protection is unknown. A monoclonal IgA directed against the V. cholerae lipopolysaccharide (LPS), secreted into the intestines of neonatal mice bearing hybridoma tumors, was previously shown to provide protection against a lethal oral dose of 10(7) V. cholerae cells. We show here that a single oral dose of 5 to 50 micrograms of the monoclonal anti-LPS IgA, given within 2 h before V. cholerae challenge, protected neonatal mice against challenge. In contrast, an oral dose of 80 micrograms of monoclonal IgA directed against CT B subunit (CTB) failed to protect against V. cholerae challenge. A total of 80 micrograms of monoclonal anti-CTB IgA given orally protected neonatal mice from a lethal (5-micrograms) oral dose of CT. Secretion of the same anti-CTB IgA antib...
Research Interests: Microbiology, Biology, Medicine, Biological Sciences, Mice, and 15 moreVibrio cholerae, Animals, Infection, Monoclonal Antibodies, Cholera, Lipopolysaccharides, Antibody, Epithelium, Cholera toxin-b, Monoclonal Antibody, Bacterial Adhesion, Small Intestine, Hybridomas, Immunoglobulin A, and Medical and Health Sciences
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1. Eur J Gastroenterol Hepatol. 1996 Jul;8(7):717-22. Frontiers in Helicobacter pylori research: pathogenesis, host response, vaccine development and new therapeutic approaches. Michetti P, Wadström T, Kraehenbuhl JP, Lee A, Kreiss C,... more
1. Eur J Gastroenterol Hepatol. 1996 Jul;8(7):717-22. Frontiers in Helicobacter pylori research: pathogenesis, host response, vaccine development and new therapeutic approaches. Michetti P, Wadström T, Kraehenbuhl JP, Lee A, Kreiss C, Blum AL. ...
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To determine the role of humoral mucosal immune response in protection against shigellosis, we have obtained a monoclonal dimeric immunoglobulin A (IgA) antibody specific for Shigella flexneri serotype 5a lipopolysaccharide (mIgA) and... more
To determine the role of humoral mucosal immune response in protection against shigellosis, we have obtained a monoclonal dimeric immunoglobulin A (IgA) antibody specific for Shigella flexneri serotype 5a lipopolysaccharide (mIgA) and used a murine pulmonary infection model that mimics the lesions occurring in natural intestinal infection. Adult BALB/c mice challenged with 10(7) S. flexneri organisms developed a rapid inflammatory response characterized by polymorphonuclear cell infiltration around and within the bronchi and strong systemic interleukin 6 response. Implantation of hybridoma cells in the back of mice, resulting in the development of a myeloma tumor producing mIgA in the serum and subsequently secretory mIgA in local secretions, or direct intranasal administration of these antibodies, protected the animals against subsequent intranasal challenge with S. flexneri serotype 5a. Absence of histopathological lesion and significant decrease in bacterial load of the lungs and...
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Research Interests: Biology, Helicobacter pylori, Medicine, Antibiotic Resistance, Humans, and 15 moreInternal Medicine, Bacterial Toxins, Escherichia coli, Enterotoxins, Animals, Clarithromycin, Clinical Sciences, Antibiotics, Gut, Asymptomatic, Metronidazole, Urease, Gastric mucosa, Paediatrics and reproductive medicine, and Medical prescription
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Infection with Helicobacter induces a T helper type 1 response in mice and humans. Mice can be cured or protected from infection with Helicobacter by mucosal immunization with recombinant H. pylori urease B subunit (rUreB). This study... more
Infection with Helicobacter induces a T helper type 1 response in mice and humans. Mice can be cured or protected from infection with Helicobacter by mucosal immunization with recombinant H. pylori urease B subunit (rUreB). This study characterizes the immune response of infected mice immunized with rUreB. BALB/c mice were infected with H. felis. Two weeks later, they were orally immunized four times with rUreB and cholera toxin (CT) at weekly intervals. Controls were only infected or sham-immunized with CT. Animals were killed at various times after immunization. Splenic CD4(+) cells were obtained and cultured in vitro with rUreB to evaluate antigen-specific proliferation and induction of interferon gamma and interleukin 4 secretion. All rUreB-immunized mice (n = 8) were cured from infection 3 weeks after the fourth immunization. Immunization induced a proliferative response of splenic CD4(+) cells, a progressive decrease in interferon gamma secretion, and a concomitant increase in interleukin 4 secretion after each immunization. A simultaneous increase in rUreB specific serum immunoglobulin G1 levels was observed in infected/immunized mice. In BALB/c mice, therapeutic mucosal immunization with rUreB induces progressively a Th2 CD4(+) T cell response resulting in the elimination of the pathogen.
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In population-based studies, up to 50% of patients with Crohn’s disease suffer from fistulas. Fistulas pose a considerable morbidity including permanent sphincter and perineal tissue destruction as well as professional and personal... more
In population-based studies, up to 50% of patients with Crohn’s disease suffer from fistulas. Fistulas pose a considerable morbidity including permanent sphincter and perineal tissue destruction as well as professional and personal disabilities. Treatment options have progressed in recent years and fistula closure and fibrosis of the fistula track is achieved in some patients. Depending on severity of symptoms and fistula location, different medical and surgical therapies can be chosen. Internal fistulas such as ileoileal or ileocecal fistulas are either asymptomatic and do not require intervention or they are symptomatic and need surgery alone. They always carry a risk of abscess formation. Symptomatic perianal fistulizing disease can be treated with antibiotics (i.e. metronidazole and ciprofloxacin) for three months and/or immunosuppressant therapy (6-mercaptopurine or azathioprine). More complex cases require therapy with anti-TNF agents. Only few and preliminary data exist on cy...
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The management of luminal Crohn’s disease, the most common form of initial presentation of the disease, depends on the location and the severity of the lesions. Mild to moderate disease represents a relatively large proportion of patients... more
The management of luminal Crohn’s disease, the most common form of initial presentation of the disease, depends on the location and the severity of the lesions. Mild to moderate disease represents a relatively large proportion of patients with a first flare of luminal disease, which may also be associated with perianal disease. As quality of life of these patients correlates with disease activity, adequate therapy is a central goal of the overall patient management. Treatment options include mainly sulfasalazine, budesonide and systemic steroids, while the role of mesalazine and antibiotics remains controversial. The role of biological therapies in mild to moderate disease has not been thoroughly evaluated and will not be discussed here.
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C hallenge experiments have been an important method of studying the pathogenesis of many infectious diseases and of evaluating initial efficacy of vaccines before large scale field tests are conducted. 2 In challenge experiments,... more
C hallenge experiments have been an important method of studying the pathogenesis of many infectious diseases and of evaluating initial efficacy of vaccines before large scale field tests are conducted. 2 In challenge experiments, infections are deliberately induced under carefully controlled and monitored conditions to healthy research volunteers. Induced infections are usually either self limiting or can be fully treated within a short period of time. Because physicians should be dedicated to alleviating disease and avoiding harm to patients, this type of experiment may cause uncomfortable symptoms and evoke serious moral concerns. It should be appreciated however that clinical research commonly involves risks to subjects that are not outweighed by medical benefits but are justified by the potential to acquire new knowledge. In that regard, infection inducing challenges are not necessarily more ethically problematic than phase I trials aimed at determining maximum tolerated doses ...
Hybridomas producing monoclonal immunoglobulin A (IgA) antibodies against Salmonella typhimurium were generated by mucosal immunization of BALB/c mice with attenuated strains of S. typhimurium and subsequent fusion of Peyer's patch... more
Hybridomas producing monoclonal immunoglobulin A (IgA) antibodies against Salmonella typhimurium were generated by mucosal immunization of BALB/c mice with attenuated strains of S. typhimurium and subsequent fusion of Peyer's patch lymphoblasts with myeloma cells. To test the role of secretory IgA (sIgA) in protection against Salmonella sp., we analyzed in detail the protective capacity of a monoclonal IgA, Sal4, produced in polymeric as well as monomeric forms, that is directed against a carbohydrate epitope exposed on the surface of S. typhimurium. BALB/c mice bearing subcutaneous Sal4 hybridoma tumors and secreting monoclonal sIgA into their gastrointestinal tracts were protected against oral challenge with S. typhimurium. This protection was directly dependent on specific recognition by the monoclonal IgA, since mice secreting Sal4 IgA from hybridoma tumors were not protected against a fully virulent mutant that lacks the Sal4 epitope. Although monoclonal Sal4 IgA was presen...
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COX-2 specific anti-inflammatory agents appear as able to induce a flare of inflammatory bowel disease as classical anti-inflammatory agents. The use of steroids, immunomodulators or infliximab prior to surgery does not appear to increase... more
COX-2 specific anti-inflammatory agents appear as able to induce a flare of inflammatory bowel disease as classical anti-inflammatory agents. The use of steroids, immunomodulators or infliximab prior to surgery does not appear to increase post-operative complication rates. Cases of hepatitis B reactivation have been described after infliximab therapy, suggesting that hepatitis B serological status should be verified prior to infliximab therapy. Adalimubab, a fully humanized antibody directed against TNF-alpha, is efficacious in patients that have lost response or did not tolerate infliximab. Approval of this agent is still awaited. Leucoapheresis is a promising tool in ulcerative colitis.
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Background Environmental factors, including sleep disturbances, have been associated with the risk of flare in inflammatory bowel disease (IBD). Symptoms, treatment side effects and pro-inflammatory status have been shown to have an... more
Background Environmental factors, including sleep disturbances, have been associated with the risk of flare in inflammatory bowel disease (IBD). Symptoms, treatment side effects and pro-inflammatory status have been shown to have an effect on sleep quality and duration. Previous studies showed that around 44% of IBD patients suffer from sleep disorders. We aimed at determining the prevalence of sleep disturbances in IBD patients, as compared with normal controls, and factors associated with disturbances. Methods We conducted a cross-sectional study on adult patients included in the Swiss IBD cohort study. We excluded pregnant women and night workers. We used the HypnoLaus cohort as a control population. Demographics, clinical, treatments, SF-36 and IBDQ (bowel, emotional, social and systemic sub-scores) quality of life data were extracted from the SIBDCS. We sent patients a questionnaire comprising the Pittsburgh Sleep Quality Index (PSQI), Epworth score (ESS), and Restless Leg Synd...
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Long-term outcome of ustekinumab in Crohn's disease (CD) has not been evaluated. To evaluate the long-term efficacy and safety of ustekinumab and identify the predictive factors of ustekinumab failure-free persistence in a cohort of... more
Long-term outcome of ustekinumab in Crohn's disease (CD) has not been evaluated. To evaluate the long-term efficacy and safety of ustekinumab and identify the predictive factors of ustekinumab failure-free persistence in a cohort of anti-TNF refractory CD patients. We performed a retrospective multicentre cohort study including all consecutive CD patients who began subcutaneous ustekinumab and presented a clinical response (defined as a significant improvement of CD-related clinical symptoms assessed by the patient's physician leading to continued ustekinumab) during the first year of treatment. Primary outcome was treatment failure defined as withdrawal of treatment due to loss of response, intolerance or need for surgery. Eighty-eight of the 122 (72%) CD patients beginning ustekinumab from March 2011 to December 2014, responded to ustekinumab and were followed up until November 2016. Median time on ustekinumab was 26.6 (13.4-34.4) months. Forty-seven patients (54%) continu...
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Research Interests: Medicine and Cohort Study
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Ustekinumab, a human monoclonal antibody against the p40 subunit of interleukins-12 and -23, is effective in inducing and maintaining remission in patients with luminal Crohn's disease (CD). We assessed the efficacy and safety of... more
Ustekinumab, a human monoclonal antibody against the p40 subunit of interleukins-12 and -23, is effective in inducing and maintaining remission in patients with luminal Crohn's disease (CD). We assessed the efficacy and safety of subcutaneous ustekinumab in patients with anti-tumor necrosis factor (anti-TNF) refractory CD. We performed a retrospective observational study, collecting data from the Groupe d'Etude Thérapeutique des Affections Inflammatoires du tube Digestif on 122 consecutive patients with active CD refractory to anti-TNF therapy who received at least 1 subcutaneous injection of ustekinumab from March 2011 to December 2014, in 20 tertiary centers in Europe. Subjects were followed for at least 3 months. The primary outcome was clinical benefit, defined as reductions in symptoms and biochemical markers of CD and complete weaning from steroids, without surgery or immunosuppressant therapies. Seventy-nine patients (65%) had a clinical benefit within 3 months of rec...