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Christophe Cellier

Publications and source records attributed to Christophe Cellier.

At least 19 recordsLinked to original sources
PubMed2006

Oral proteases: a new approach to managing coeliac disease.

A life-long but constraining gluten-free diet is the only treatment currently available for coeliac disease. The human gastrointestinal tract does not possess the enzymatic equipment to efficiently cleave the gluten-derived proline-rich peptides driving the abnormal immune intestinal response in patients with coeliac disease. Oral therapy by exogenous prolylendopeptidases able to digest ingested gluten was therefore propounded as an alternative treatment to the diet. The feasibility of this approach is discussed by reviewing recent data on the intestinal transport of gliadin peptides, properties of available enzymes and preliminary clinical assays. Development of new enzymes or enzymatic cocktails offers potentially more potent therapeutic tools that, however, need meticulous evaluation based on clinical, biological and histological criteria.

Administration, Oral↗
PubMed2006

Adulthood-onset celiac disease is associated with intercellular adhesion molecule-1 (ICAM-1) gene polymorphism.

Celiac disease (CD) is a multifactorial T-cell-mediated autoimmune disease characterized by gluten-triggered villous atrophy and malabsorption. Although human leukocyte antigen (HLA) class II genes are strong susceptibility factors, non-HLA genes likely contribute to most of CD predisposition. The intercellular adhesion molecule-1 (ICAM-1) gene is a good candidate for CD predisposition because its encoded protein acts as an adhesion and costimulatory receptor. Two single-base polymorphisms (G/A in exon 4 encoding G241R, and A/G in exon 6 encoding K469E) were analyzed in 180 French Caucasian CD case patients (110 patients diagnosed before the age of 15 and 70 patients after the age of 18), and 212 French Caucasian healthy controls. The R241 allele frequency was increased in CD case patients compared with controls (14.2% vs. 5.4% respectively, p = 0.000015, odds ratio [OR] for the R241 allele = 2.9, 95% confidence intervals [CI] = 1.7-4.8). After stratifying for age of disease onset, the R241 variant mainly conferred predisposition to CD occurring during adulthood (OR = 4.2, 95% CI = 2.3-7.5, Pc = 0.000004 for adulthood-onset CD vs. R = 2.1, 95%, CI = 1.2-3.9, Pc = 0.0047 for childhood-onset CD). Position 241 of ICAM-1 maps to the binding site for the integrin Mac-1 and might modify the strength of interaction between endothelium and immune cells. If confirmed in independent datasets, these results may be of importance in at-risk individuals to distinguish rapid from delayed progression to clinical CD.

Adolescent↗
PubMed2005

Refractory coeliac disease.

A small proportion of coeliac disease (CD) patients fail to improve after a gluten-free diet (GFD) and may be considered as atypical regarding their outcome (refractory coeliac disease). The aim of this study is to diagnose and manage patients with CD who fail to improve after a GFD. Refractory coeliac disease (RCD) is a malabsorption syndrome defined by persisting villous atrophy with, usually, an increase of intraepithelial lymphocytes (IELs) in the small bowel in spite of a strict GFD and comprises a heterogenous group of diseases. Some of these diseases have to be excluded and can be treated by specific therapies like antibiotics in tropical sprue and giardiasis and immune globulin substitution in common variable immunodeficiency, while other malabsorption syndromes are less well defined and may require immunosuppressive therapy. Standardized treatment, however, has not been evaluated in such patients so far. In a subgroup of patients with RCD, an abnormal intraepithelial lymphocyte (IEL) population may be observed with the lack of surface expression of usual T-cell markers (CD3-CD8 and/or the T-cell receptor (TCR)) on IELs associated with T-cell clonality pattern suggest the presence of an early enteropathy-associated T-cell lymphoma (EATL) in a subgroup of patients with RCD. This hypothesis has been supported by studies, which revealed progression into overt intestinal T-cell lymphomas in a subgroup of RCD. Steroid treatment has been reported effective even in patients with underlying early EATL. However, long-term results are unsatisfactory in most of these patients with RCD and parenteral nutrition has to be applied in some of these cases. First results with more aggressive chemotherapies and use of cytokines are under way. Due to the difficulty of diagnostic and therapeutic regimens patients should be referred to tertiary centres for coeliac disease.

Celiac Disease↗
PubMed2005

The European experience with double-balloon enteroscopy: indications, methodology, safety, and clinical impact.

BACKGROUND: Double-balloon enteroscopy (DBE) is a new technique that allows high-resolution visualization, biopsies, and therapeutic interventions in all segments of the GI tract. The objective of the study was to evaluate the indications, the safety, and the clinical impact of DBE. METHODS: This is a retrospective analysis conducted at 4 European medical centers. A total of 62 patients with suspected or documented small-bowel diseases were investigated by DBE. A total of 89 procedures were performed (26 and 9 patients from the oral or the anal route, respectively; 27 patients from both). The main outcome measurements were complications, depth and time of insertion, diagnostics, and therapeutics rates. RESULTS: No complications occurred. Mean time was 70 +/- 30 minutes and 90 +/- 35 minutes from the oral and the anal route, respectively. Length of insertion was 254 +/- 174 cm beyond the pylorus, 180 +/- 150 cm beyond the ileocecal valve, whereas the entire small bowel was completely explored in 10 patients. DBE was diagnostic in 80% of the patients: in 29 of 33 of patients with GI bleeding, in one of 5 patients with iron deficiency anemia and positive fecal occult blood testing, in 3 of 5 patients with chronic diarrhea, in two of 3 patients with abdominal pain, in two of 3 patients with GI cancer (follow-up), in all patients with suspected or refractory celiac disease, and in two of 3 patients with Crohn's disease. Treatment was performed in 41.9% of patients (22 polyps and 29 angioectesias). CONCLUSIONS: DBE is a safe and feasible diagnostic and therapeutic tool for suspected or documented small-bowel diseases. At present, the best candidates for the procedure appear to be those with obscure GI bleeding.

Endoscopes, Gastrointestinal↗
PubMed2005

Predictive factors of positive findings in patients explored by push enteroscopy for unexplained GI bleeding.

BACKGROUND: The diagnostic yield of push enteroscopy (PE) in patients with unexplained overt GI bleeding is about 30%. The aim of this study was to assess for predictive factors of positive findings. METHODS: A total of 182 patients referred to two endoscopic centers (European Georges Pompidou Hospital [Paris, France] and Erasmus Hospital [Brussels, Belgium]) for unexplained overt GI bleeding (melena [57%], hematochezia [26%], or hematochezia associated with melena [17%]) were included in this retrospective study. Predictive factors associated with positive findings at upper PE were studied by using uni- and multivariate analysis. RESULTS: The overall diagnostic yield of upper PE was 34% (62/182), but lesions were found beyond the second duodenum in 25% of the patients (45/182). Factors significantly associated with positive findings at upper PE were the following. (1) In univariate analysis: the presence of melena, Hb level <7 g/dL, blood transfusion >4 units per patient, chronic renal failure, disorder of hemostasis or effective anticoagulant treatment, history of intestinal arteriovenous malformation, and age > 65 years. (2) In multivariate analysis: chronic renal failure and presence of melena. If only jejunal lesions were considered, chronic renal failure was the only predictive factor associated with positive findings at upper PE in multivariate analysis. The severity of GI bleeding did not reach statistical significance ( p = 0.06). Delay between GI bleeding and PE, number of previous standard endoscopies and previous episodes of bleeding were not associated with positive findings in upper PE. CONCLUSIONS: In patients with unexplained overt GI bleeding, upper PE has a higher diagnostic yield in patients with chronic renal failure and patients with melena (vs. hematochezia).

Adolescent↗
PubMed2005

Abnormal appearance of the internal anal sphincter at ultrasound: a specific feature of progressive systemic sclerosis?

Endosonography is now an effective tool for the assessment of anorectal pathologies. We present a case of rectal prolapse in a patient with progressive systemic sclerosis, with low resting anal pressure, no rectoanal inhibitory reflex in manometry, and a thin, heterogeneous, difficult to delineate, internal sphincter on endoanal ultrasound. We also provide a review of the literature on anorectal involvement in progressive systemic sclerosis.

Anal Canal↗
PubMed2005

Chromoendoscopic colonoscopy for detecting preneoplastic lesions in hereditary nonpolyposis colorectal cancer syndrome.

BACKGROUND & AIMS: In hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, flat and small adenomas are particularly prone to malignant transformation but might be missed by standard colonoscopy. We prospectively studied the diagnostic yield of high-resolution colonoscopy coupled with chromoendoscopy for preneoplastic and neoplastic colorectal lesions in patients with HNPCC syndrome. METHODS: Thirty-six consecutive asymptomatic patients (mean age, 42 years) belonging to HNPCC families and receiving genetic counseling were enrolled in this prospective study. Colonoscopy was performed in 2 steps. Conventional colonoscopy was performed first, followed by a second colonoscopy with chromoendoscopy with indigo carmine (.4%) dye sprayed onto the entire proximal colon. RESULTS: Conventional colonoscopy identified 25 lesions (mean size, 4 +/- 3 mm) in 13 patients. Seven lesions, detected in 5 patients, were adenomas, 3 of which were located in the proximal colon. Chromoendoscopy identified additional 45 lesions (mean size, 3 +/- 1 mm) in 20 patients; most of these lesions were flat and hyperplastic. Eleven additional adenomas were detected in the proximal colon of 8 patients, and 8 of these 11 lesions were flat. The use of chromoendoscopy significantly increased the detection rate of adenomas in the proximal colon, from 3 of 33 patients to 10 of 33 patients (P = .045). CONCLUSION: Relative to conventional colonoscopy, high-resolution colonoscopy with chromoendoscopy markedly improves the detection of adenomas in patients with HNPCC syndrome and might help to prevent colorectal carcinoma in these patients with a very high risk of colorectal cancer.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Limited efficiency of prolyl-endopeptidase in the detoxification of gliadin peptides in celiac disease.

BACKGROUND & AIMS: The resistance of prolamines to digestive enzymes is thought to be a key contributor to the pathogenesis of celiac disease by promoting the intestinal entrance of peptides able to trigger inflammation in at-risk individuals. Oral administration of a bacterial prolyl-endopeptidase (PEP) therefore was proposed as a treatment for celiac disease. To delineate the feasibility of this treatment, the effect of PEP on gliadin peptides was assessed in vitro, and ex vivo during their transport across intestinal biopsy specimens of active celiac disease patients. METHODS: In vitro degradation by PEP of 3H-labeled gliadin peptides 56-88 (33-mer) and 31-49, was analyzed by radio-reverse-phase high-performance liquid chromatography and mass spectrometry. For ex vivo studies, PEP and 3H-peptides were added together onto the mucosal side of duodenal biopsy specimens mounted in Ussing chambers, and peptide transport and digestion were assessed by radio-reverse-phase high-performance liquid chromatography. RESULTS: Gliadin peptides were degraded partly by 20 mU/mL PEP both in vitro and ex vivo. This concentration of PEP decreased the amount of intact peptides 31-49 and 56-88 crossing the intestinal biopsy specimens of celiac disease patients, but could not prevent the intestinal passage of toxic or immunostimulatory metabolites. PEP concentrations of at least 500 mU/mL for 3 hours were required to achieve full detoxification of peptides and to prevent intestinal transport of active fragments. CONCLUSIONS: After prolonged exposure to high concentrations of PEP, the amount of immunostimulatory gliadin peptides reaching the local immune system in celiac patients is decreased. These results provide a basis to establish whether such conditions are achievable in vivo.

Biopsy↗
PubMed2004

A direct role for NKG2D/MICA interaction in villous atrophy during celiac disease.

MICA molecules interact with the NKG2D-activating receptor on human NK and CD8 T cells. We investigated the participation of the MICA/NKG2D pathway in the destruction of intestinal epithelium by intraepithelial T lymphocytes (IEL) in Celiac disease and its premalignant complication, refractory sprue. We show that MICA is strongly expressed at epithelial cell surface in patients with active disease and is induced by gliadin or its p31-49 derived peptide upon in vitro challenge, an effect relayed by IL-15. This triggers direct activation and costimulation of IEL through engagement of NKG2D, leading to an innate-like cytotoxicity toward epithelial targets and enhanced TCR-dependent CD8 T cell-mediated adaptive response. Villous atrophy in Celiac disease might thus be ascribed to an IEL-mediated damage to enterocytes involving NKG2D/MICA interaction after gliadin-induced expression of MICA on gut epithelium. This supports a key role for MIC/NKG2D in the activation of intraepithelial immunity in response to danger.

Atrophy↗
PubMed2004

Relationship of HLA-DQ8 and severity of celiac disease: comparison of New York and Parisian cohorts.

BACKGROUND & AIMS: Celiac disease is a polygenic disorder associated with HLA-DQ2 or HLA-DQ8, which are present in greater than 90% of patients. The disease is considered milder in the United States compared with Europe. We assessed whether differences in the frequency of HLA type may account for differences in severity of the disease by using cohorts of patients from New York and Paris. METHODS: HLA-DQ typing was performed on patients with celiac disease in New York and Paris. Clinical and pathologic data were compared between the New York and Parisian cohorts and also correlated with the different HLA types (HLA-DQ2, HLA-DQ2/-DQ8, HLA-DQ8). RESULTS: Among these patients, the disease was milder in the New York cohort compared with the Parisian cohort. There were fewer patients with a classical presentation (45% and 89%, respectively; P < 0.001) and less severe pathology (total villous atrophy, 64% and 89%, respectively; P < 0.05), and less marked intraepithelial lymphocytosis (intraepithelial leukocytes [IELs]/100 enterocytes, 48.1 and 82.5, respectively; P < 0.0001). HLA-DQ2 homozygotes were less prevalent in the New York cohort compared with the Parisian cohort (59% and 79%, respectively; P = 0.08). HLA-DQ8 alleles were more prevalent in the New York cohort compared with the Parisian cohort (41% and 21%, respectively; P = 0.026). There was, however, no difference in the clinical or pathologic parameters of severity when we compared the groups based on HLA type. CONCLUSIONS: HLA-DQ8 alleles were increased in the New York cohort of patients with celiac disease; however, this did not account for less severe manifestations of the disease.

Adult↗
PubMed2004

Clinical impact of push enteroscopy in patients with gastrointestinal bleeding of unknown origin.

BACKGROUND & AIMS: Despite the frequent use of push enteroscopy (PE), little is known of its clinical impact. The aim of this study was to evaluate the impact of PE on diagnostic and therapeutic management of patients with gastrointestinal bleeding of unknown origin. METHODS: Seventy-five consecutive patients (mean age, 56 y) referred for PE were included in this 1-year prospective study. Indications for PE were overt bleeding in 46 patients (61%) and iron-deficiency anemia in 29 patients (39%). Before the procedure, the prescribing physicians were asked to fill out a questionnaire listing the theoretical patient management plan (diagnostic procedures and/or treatment) as if PE were not available. One month after PE, the same physicians were asked about: (1) diagnostic procedures performed after PE, (2) the final diagnosis, and (3) their opinion of the usefulness of PE in clinical management. The clinical impact of PE on diagnostic and/or therapeutic management was assessed by 3 study physicians. RESULTS: Responses to the 2 questionnaires were obtained for all patients. The diagnostic yield of PE was 32% (24 of 75). The clinical impact of PE (changes in diagnostic and/or therapeutic management) was 55% (n = 41). PE was perceived as helpful by the prescribing physicians in 55% of cases. PE tended to influence patient management more in cases of overt bleeding than in cases of occult bleeding (63% vs. 41%; P = 0.06). CONCLUSIONS: PE influenced the clinical management of more than half the patients with GI bleeding of unknown origin, and was particularly useful in patients with overt bleeding.

Adolescent↗
PubMed2003

Recurrent partial trisomy 1q22-q44 in clonal intraepithelial lymphocytes in refractory celiac sprue.

BACKGROUND & AIMS: Refractory celiac sprue, a low-grade intraepithelial lymphoma characterized by expansion of clonal intraepithelial lymphocytes with intracellular CD3 epsilon but no surface CD3-T-cell receptor complexes, can be an intermediary step between celiac disease and overt T-cell lymphoma. To gain insight into the mechanisms of lymphomagenesis in celiac disease, we have performed the first cytogenetic study in refractory celiac sprue. METHODS: Karyotypes were performed on: (1) 7 cell lines derived from clonal intraepithelial lymphocytes of patients with refractory celiac sprue; (2) 14 control T-cell lines, either from 4 of 7 patients with refractory celiac sprue or from 10 patients with uncomplicated celiac disease; and (3) bone marrow and peripheral blood lymphocytes in 1 of 7 patients with refractory celiac sprue. Rearrangements were confirmed by in situ hybridization using whole-chromosome painting probes and by comparative genomic hybridization in one patient. RESULTS: A recurrent structural chromosomal aberration leading to partial trisomy of the long arm of chromosome 1 was found in 6 of 7 cell lines from patients with refractory celiac sprue but in none of the control T-cell lines. In one patient with circulating abnormal intraepithelial lymphocytes, the partial trisomy 1q was confirmed on cells freshly isolated from bone marrow and blood. CONCLUSIONS: Refractory celiac sprue is strongly associated with partial trisomy of the 1q region. Gain of chromosome 1q, recently found in 16% of enteropathy-type T-cell lymphoma, may be an early event in lymphomagenesis related to celiac disease and provides a key to investigating molecular mechanisms of lymphoid transformation in this disease.

Adult↗
PubMed2003

Alterations of the intestinal transport and processing of gliadin peptides in celiac disease.

BACKGROUND & AIMS: The hypothesis of a defect in the intestinal transport and processing of toxic (31-49) or immunostimulant (57-68 and the 33-mer 56-89) gliadin peptides was tested in patients with active celiac disease (ACD), patients with treated celiac disease (TCD), and controls. METHODS: Using duodenal biopsy specimens mounted in Ussing chambers, we measured electrical resistance, mucosal-to-serosal radiolabeled-peptide fluxes, and peptide processing during transport using radio-reverse-phase high-performance liquid chromatography. RESULTS: Peptide 31-49 fluxes (24.7 microg x 3 h(-1). cm(-2)) were increased in patients with ACD compared with controls and patients with TCD (12.7 and 12.3 microg x 3 h(-1). cm(-2); P < 0.01). In contrast, no increase was observed for peptide 57-68 or 56-89 (33-mer). Electrical resistance was decreased in patients with ACD versus controls (15.3 vs. 23.9 ohms. cm(2); P < 0.001). Peptide 57-68 was partially degraded by brush-border peptidases in controls but not in patients with celiac disease. However, it was totally degraded after intestinal transport both in controls and patients with celiac disease. Peptides 31-49 and 56-89 were resistant to brush-border peptidases in all groups of patients but were totally degraded during intestinal transport in controls and patients with TCD. In patients with ACD, however, 50% of peptide 31-49 was delivered intact into the serosal compartment and only partial degradation of the 33-mer was observed. These abnormalities were not related to a nonspecific paracellular leakage. CONCLUSIONS: Our data indicate that gliadin peptides, although poorly or not digested by intraluminal enzymes, can be fully digested by enterocytes in controls and patients with TCD. In patients with ACD, incomplete degradation of the 33-mer and protected transport of the peptide 31-49 might favor their respective immunostimulatory and toxic effects.

Adult↗