Marc Ferrante

McGill University Health Centre, Montréal, Quebec, Canada

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Publications (93)552.65 Total impact

  • Journal of Crohn's and Colitis. 01/2014; 8:S8.
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    ABSTRACT: Background A long-lasting good functional outcome of the pelvic pouch and a subsequent satisfying quality of life (QoL) are mandatory. Long-term functional outcome and QoL in a single-center cohort were assessed. Patients and methods A questionnaire was sent to all patients with an IPAA for UC, operated between 1990 and 2010 in our department. Pouch function was assessed using the Öresland Score (OS) and the ‘Pouch Functional Score’ (PFS). QoL was assessed using a Visual Analogue Score (VAS). Results 250 patients (42% females) with a median age at surgery of 38 years (interquartile range (IQR): 29–48 years) underwent restorative proctocolectomy. Median follow‐up was 11 years (IQR: 6–17 years). Response rate was 81% (n = 191). Overall pouch function was satisfactory with a median OS of 6/15 (IQR: 4–8) and a median PFS of 6/30 (IQR: 3–11). 24-hour bowel movement is limited to 8 times in 68% of patients (n = 129), while 55 patients (29%) had less than 6 bowel movements. 12 patients (6.5%) were regularly incontinent for stools, while 154 patients (82%) reported a good fecal continence. Fecal incontinence during nighttime was more common (n = 72, 39%). Pouch function had little impact on social activity (4/10; IQR: 2–6) and on professional activity (3/10; IQR: 1–6). 172 patients (90%) reported to experience an overall better health condition since their operation. The OS and the PFS correlated well (Pearson's correlation coefficient = 0.83). Overall pouch function was stable over time. Conclusion Majority of patients report a good pouch function on the long-term with limited impact on QoL.
    Journal of Crohn s and Colitis 01/2014; · 3.39 Impact Factor
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    ABSTRACT: Matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), a disintegrin and metalloprotease with thrombospondin motifs [ADAM(TS)s] and growth factors are involved in inflammation and tissue damage and repair, all occurring in inflammatory bowel disease (IBD). We studied the impact of anti-inflammatory therapy with infliximab on mucosal expression of these tissue remodeling genes in patients with IBD. Mucosal gene expression of 23 MMPs, 4 TIMPs, 50 ADAM(TS)s, and 158 growth factors was investigated in 61 patients with IBD before and after the first infliximab therapy and in 12 controls, with microarrays and quantitative RT-PCR. Protein localization, mucosal gelatinase levels, and net gelatinolytic activity were investigated by immunohistochemistry, zymography analysis, and gelatin degradation assay, respectively. In patients with active IBD before infliximab versus controls, gene expression of many MMPs, TIMPs, ADAM(TS)s, and growth factors was upregulated, whereas colonic expression of MMP28 and TGFA and ileal expression of ADAMDEC1 and AGT were downregulated. After controlling inflammation with infliximab, most gene dysregulations observed at baseline were restored in responders. Increased ratio of MMP1/TIMP1 expression at baseline in active IBD was restored in responders with colonic mucosal healing. With immunohistochemistry, protein localization differences of MMP1, MMP3, REG1A, and TIMP1 were shown between active IBD and control mucosa. With zymography analysis and gelatin degradation assay, higher gelatinase levels and net gelatinolytic activity were measured before infliximab and levels normalized after infliximab. Our data suggest that suppression of inflammation results in the arrest of epithelial damage and subsequent mucosal healing. Therefore, the therapeutic potential of agents targeting MMPs or growth factors as primary therapy seems rather complex.
    Inflammatory Bowel Diseases 12/2013; · 5.12 Impact Factor
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    ABSTRACT: ABO encodes a glycosyltranferase which determines the major human histo-blood group. The FUT2 fucosyltransferase allows expression of ABO antigens on the gastrointestinal mucosa and in bodily secretions (secretor phenotype). A nonsense allele in FUT2 represents a susceptibility variant for Crohn's disease, and both the secretor and ABO blood group status affect the composition of the gut microbiota. Thus, we evaluated if variants in ABO might represent good candidates as Crohn's disease susceptibility loci. We recruited two case-control cohorts, from Italy (n=1301) and Belgium (n=2331). Subjects were genotyped for one SNP in FUT2 and two variants in ABO. No effect on Crohn's disease risk was detected for ABO variants, whereas an association was observed between the FUT2 polymorphism and Crohn's disease susceptibility in the Belgian sample, but not in the Italian cohort. The effect of histo-blood groups was evaluated using group O as the reference. Most non-O groups had odds ratios (ORs) higher than 1 in both cohorts, and combined analysis of the two samples indicated a predisposing effect for the A and B groups (OR=1.17, 95% CI: 1.02-1.32 and OR=1.33, 95% CI: 1.09-1.58, respectively). In Crohn's disease patients, the non-O blood group and the non-secretor status were associated with higher risk of developing a stricturing or penetrating disease. ABO histo-blood group might confer susceptibility to Crohn's disease and modulate disease severity.
    Journal of Crohn s and Colitis 11/2013; · 3.39 Impact Factor
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    ABSTRACT: Introduction: The advent of tumor necrosis factor (TNF) antagonists represented a radical change in the management of inflammatory bowel disease (IBD). Both in short- and long-term, anti-TNF therapy has been shown to reduce symptoms, heal mucosal ulcers, reduce hospitalizations and surgeries and spare corticosteroids. Areas covered: A literature search to August 2013 was performed to identify the most relevant reports on the use of TNF antagonists in IBD. First, the authors focused on the mechanism of action of TNF antagonists. Second, they evaluated different indications, contraindications, the optimal time to start and the role of combining TNF antagonists with immunomodulators. Third, they explored the importance of mucosal healing, followed by the controversial topic on when TNF antagonists should be stopped. This is followed by the subjects of treatment failure, immunogenicity and therapeutic drug monitoring. Last, they analyzed safety issues including exposure to TNF antagonists during pregnancy. Expert opinion: TNF antagonists have become indispensable in the management of IBD. Efforts to focus on treatment of inflammatory signs only and on optimization of treatment with therapeutic drug monitoring are underway. The advent of several new compounds and "biosimilars" will further challenge the position of TNF antagonists in the treatment algorithm of IBD.
    Expert opinion on biological therapy 11/2013; · 3.22 Impact Factor
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    Journal of Gastroenterology 11/2013; 145:978-986. · 3.79 Impact Factor
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    ABSTRACT: Introduction: The introduction of antibodies directed against tumor necrosis factor (anti-TNF) has dramatically changed our concept of treating both patients with Crohn's disease (CD) and patients with rheumatoid arthritis (RA). Subcutaneous injections with certolizumab pegol (CZP) have been shown efficacious for both CD and RA. In this review, the authors focus on the safety of CZP among other anti-TNF agents. Areas covered: A literature search till June 2013 was performed to identify all trials studying CZP in patients with CD and RA. In addition, abstracts of major congresses were assessed. The authors first focused on the mechanism of action of CZP, and evaluated the efficacy of this drug in both CD and RA. Next, they explored the available safety data on CZP, including infection and malignancy risk, injection site reactions, the development of antibodies against CZP, as well as its use during pregnancy. Expert opinion: Based on the provided literature, CZP seems to have a similar safety profile to other anti-TNF agents. However, in young females considering pregnancy, CZP may be advocated over other anti-TNF agents as it does not actively cross the placenta.
    Expert Opinion on Drug Safety 10/2013; · 2.62 Impact Factor
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    ABSTRACT: Several aspects of the management of Crohn's disease (CD) are shared between patients. The goal of all therapies should be to achieve clinical and endoscopic remission in a timely manner to avoid disease progression and abdominal resections. The way this goal is achieved may differ and predicting how the disease will evolve, what the most appropriate therapy with the highest chance of success will be, how long a therapy needs to be continued, and what the intensity of follow-up should be are more difficult questions and require an individualised approach. Clinical parameters have been suggested to aid in the therapeutic decision process but lack specificity. Although much promise has been put in molecular markers, these have not yet found their way to the clinic. More recently, clinicians have started to gain interest in drug level monitoring to adapt doses of immunomodulators and/or anti-tumour necrosis factor antibodies in an individualised manner. An increasing number of studies show that therapeutic drug monitoring can help physicians to improve and personalise the management of their patients. What is needed now are pharmaco-economic studies showing that personalised management of CD is cost effective.
    Gut 10/2013; 62(10):1511-5. · 10.73 Impact Factor
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    ABSTRACT: Bacteria play an important role in the onset and perpetuation of intestinal inflammation in inflammatory bowel disease (IBD). Unlike in Crohn's disease (CD), in which dysbiosis has been better characterised, in ulcerative colitis (UC), only small cohorts have been studied and showed conflicting data. Therefore, we evaluated in a large cohort if the microbial signature described in CD is also present in UC, and if we could characterise predominant dysbiosis in UC. To assess the functional impact of dysbiosis, we quantified the bacterial metabolites. The predominant microbiota from 127 UC patients and 87 age and sex-matched controls was analysed using denaturing gradient gel electrophoresis (DGGE) analysis. Differences were quantitatively validated using real-time PCR. Metabolites were quantified using gas chromatography-mass spectrometry. Based on DGGE analysis, the microbial signature previously described in CD was not present in UC. Real-time PCR analysis revealed a lower abundance of Roseburia hominis (p<0.0001) and Faecalibacterium prausnitzii (p<0.0001) in UC patients compared to controls. Both species showed an inverse correlation with disease activity. Short-chain fatty acids (SCFA) were reduced in UC patients (p=0.014), but no direct correlation between SCFA and the identified bacteria was found. The composition of the fecal microbiota of UC patients differs from that of healthy individuals: we found a reduction in R hominis and F prausnitzii, both well-known butyrate-producing bacteria of the Firmicutes phylum. These results underscore the importance of dysbiosis in IBD but suggest that different bacterial species contribute to the pathogenesis of UC and CD.
    Gut 09/2013; · 10.73 Impact Factor
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    ABSTRACT: Mucosal healing might alter mid- and long-term outcomes of patients with Crohn's disease (CD) and has become an important endpoint in clinical trials. However, the minimal degree of mucosal improvement (endoscopic response) required to alter mid-term outcomes is not known. We aimed to determine the best definition of endoscopic response by evaluating the simple endoscopic score for CD (SES-CD) and the CD endoscopic index of severity (CDEIS) from the study of biologic- and immunomodulator-naive patients in CD (SONIC trial). We analyzed data from 172 patients who participated in the SONIC trial, were found to have endoscopic lesions at baseline, and underwent a second endoscopic examination at week 26 of treatment with infliximab, azathioprine, or both. Mucosal healing was defined as absence of ulcers. A central reader calculated SES-CD and CDEIS results. Different cut-off values were set for endoscopic response, based on the SES-CD or CDEIS. The diagnostic ability of these different cut-off values were evaluated using receiver operating characteristic (ROC) curves and positive (PLR) and negative likelihood ratios (NLR). Corticosteroid-free clinical remission (CFREM) at week 50 was used as a binary classifier. Based on analyses of ROC curves, PLR, and NLR, endoscopic response was defined as a decrease from baseline in SES-CD of at least 50%. At week 26, mucosal healing and endoscopic response were achieved in 48% and 65% of patients, respectively. Mucosal healing at week 26 was associated with CFREM at week 50, with 56% sensitivity, 65% specificity, a PLR of 1.60, and an NLR of 0.67. Endoscopic response at week 26 was associated with CFREM at week 50, with 74% sensitivity, 48% specificity, a PLR of 1.42, and an NLR of 0.54. Endoscopic response, defined as a decrease from baseline in CDEIS of at least 50%, yielded similar results. In patients with CD, mucosal healing and endoscopic response (defined as a decrease from baseline in SESCD or CDEIS of at least 50%) at week 26 of treatment identified those most likely to be in CFREM at week 50. The ability of the proposed endoscopic response cut-off value to predict mid-term CFREM should be validated in an independent, prospective cohort. Its correlation with changes in long-term disease progression requires demonstration. Clinical trials.gov, Number: NCT00094458.
    Gastroenterology 08/2013; · 12.82 Impact Factor
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    ABSTRACT: Introduction: Chronically relapsing inflammation, tissue remodeling and fibrosis are hallmarks of inflammatory bowel diseases. The aim of this study was to investigate changes in connective tissue in a chronic murine model resulting from repeated cycles of dextran sodium sulphate (DSS) ingestion, to mimic the relapsing nature of the human disease. Materials and Methods: C57BL/6 mice were exposed to DSS in drinking water for 1 week, followed by a recovery phase of 2 weeks. This cycle of exposure was repeated for up to 3 times (9 weeks in total). Colonic inflammation, fibrosis, extracellular matrix proteins and colonic gene expression were studied. In vivo MRI T2 relaxometry was studied as a potential non-invasive imaging tool to evaluate bowel wall inflammation and fibrosis. Results: Repeated cycles of DSS resulted in a relapsing and remitting disease course, which induced a chronic segmental, transmural colitis after 2 and 3 cycles of DSS with clear induction of fibrosis and remodeling of the muscular layer. Tenascin expression mirrored its expression in Crohn’s colitis. Microarray data identified a gene expression profile different in chronic colitis from that in acute colitis. Additional recovery was associated with upregulation of unique genes, in particular keratins, pointing to activation of molecular pathways for healing and repair. In vivo MRI T2 relaxometry of the colon showed a clear shift towards higher T2 values in the acute stage and a gradual regression of T2 values with increasing cycles of DSS. Conclusions: Repeated cycles of DSS exposure induce fibrosis and connective tissue changes with typical features, as occurring in Crohn’s disease. Colonic gene expression analysis revealed unique expression profiles in chronic colitis compared to acute colitis and after additional recovery, pointing to potential new targets to intervene with the induction of fibrosis. In vivo T2 relaxometry is a promising non-invasive assessment of inflammation and fibrosis.
    PLoS ONE 07/2013; 8(7):e68876. · 3.73 Impact Factor
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    ABSTRACT: Increased lymphatic vessel (LV) density has been found in uninflamed intestinal wall of patients with Crohn's disease (CD). The goal of the study was to search for an association between LV density in the proximal ileal resection margin at the time of surgery and endoscopic recurrence. Ileocolonic resection specimens were obtained from 28 CD patients and 10 control subjects. The ileal proximal uninflamed section was used for the histological quantification of LV using immunohistochemistry with D2-40 antibody in the mucosa and submucosa. Quantification of LV was performed in 8 consecutive fields and was blinded to recurrence score. Patients were divided into 2 groups based on the presence (Rutgeerts score, i3/i4) (R+) or absence (Rutgeerts score, i0/i1) (R-) of endoscopic recurrence 1 year after the surgery. All patients were free of immunomodulators or biologics between surgery and postoperative endoscopy. Median LV density was lower in control subjects than in CD patients in the mucosa (4.5%; interquartile range [IQR], 3.6-5.3 versus 5.9%; IQR, 4.2-8.5; P = 0.04) and submucosa (2.4%; IQR, 1.9-3.6 versus 5.7%; IQR, 4.3-6.9; P < 0.01). R- patients had a higher LV density in the proximal resection margin at surgery than R+ patients, both in the mucosa (8.5%; IQR, 6.5-10.3 versus 4.4%; IQR, 3.1-6.1; P < 0.01) and in the submucosa (6.3%; IQR, 5.5-9.3 versus 5.3%; IQR, 3.4-5.9; P = 0.03). Mucosal LV density greater than 7% predicted the absence of endoscopic recurrence at 1 year, with a sensitivity of 81% and a specificity of 75%. Decreased LV density is associated with high risk of endoscopic recurrence after surgery. Therapies that improve lymphatic flow in the gut may reduce the incidence of endoscopic recurrence.
    Inflammatory Bowel Diseases 07/2013; · 5.12 Impact Factor
  • The American Journal of Gastroenterology 06/2013; 108(6):1015. · 7.55 Impact Factor
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    ABSTRACT: BACKGROUND AND AIM: Pain and nausea are often reported during bowel cleansing (BC) for ileocolonoscopy (IC). We aimed to explore putative mechanisms associated with impaired tolerance to BC. METHODS: A 1:1 (100 IBD and 100 controls) sex and age matched case-control study was performed. Patients completed the hospital anxiety and depression scale (HADS-A/HADS-D), visceral sensitivity index (VSI) and state-trait anxiety inventory, state scale (STAI-S), in addition to self-assessment of BC and abdominal pain and nausea ratings during BC. Endoscopists reported the Mayo score, Harvey Bradshaw index (HBI), simple endoscopic score for Crohn's disease, and Boston bowel preparation scale (BBPS). RESULTS: Higher VSI and depression scores were observed in IBD patients. VSI (P<0.0001) and age (P=0.008) showed a positive and negative association with abdominal pain during BC, respectively. HADS-A (P=0.009) and female sex (P=0.02) were positively associated with nausea during BC, while age (P=0.02) showed a negative association. Disease activity was not associated with worse BBPS or nausea during BC, while a higher HBI was associated with more pain during BC (P=0.0006). Nausea (P=0.007) and abdominal pain (P=0.003) during BC, and less previous ICs (P=0.03) were independently associated with anxiety prior to IC (STAI-S). Significant correlations were found between VSI and STAI-S and disease activity. CONCLUSION: Higher gastrointestinal-specific anxiety and co-morbid anxiety are associated with increased pain and nausea during BC, respectively. Pain and nausea during BC were in turn associated with higher anxiety levels at the moment of IC, potentially creating a "vicious circle". Measures taken to reduce anxiety could improve BC and IC tolerance.
    Journal of Crohn s and Colitis 05/2013; · 3.39 Impact Factor
  • Alimentary Pharmacology & Therapeutics 05/2013; 37(10):1024-1025. · 4.55 Impact Factor
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    ABSTRACT: BACKGROUND:: In routine practice, scoring of activity and severity of ulcerative colitis is based on combined clinical and endoscopic assessment. Histology also allows sensitive scoring of ulcerative colitis activity. The correlation between endoscopy and histology has not been investigated thoroughly. It is still unknown how well they correlate and whether scoring both endoscopy and histology better reflects the true disease activity than each of the methods separately. METHODS:: Two hundred and sixty-three biopsy sets from 131 known patients with ulcerative colitis were reviewed by an experienced gastrointestinal pathologist and scored using the Geboes and Riley histologic scoring systems. Endoscopic scoring had been performed previously by inflammatory bowel disease specialists using the Mayo endoscopic subscore. Bidirectional comparison of the Mayo endoscopic subscore with the full and converted histologic scores was then performed. RESULTS:: We found a statistically significant overall correlation between the Mayo endoscopic subscore and the histologic scores (highest correlation: Kendall's τ = 0.482, P < 0.0001). Although a very high concordance was found for inactive and severely active disease, a high diversity was detected between these extremes. For example, endoscopic mildly active disease (Mayo 1) was distributed over all different histologic grades (37%, grade 0; 21%, grade 1; 28%, grade 2; and 14%, grade 3). CONCLUSIONS:: Both extremes of the histologic and endoscopic activity scores neatly correlate, but important misclassifications exist for mild disease. Microscopy may detect more severe disease than endoscopically suspected, possibly altering the clinical follow-up scheme. We also infer from our results that histologic scoring should be used in addition to endoscopy when scoring disease activity for clinical trials.
    Inflammatory Bowel Diseases 03/2013; · 5.12 Impact Factor
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    ABSTRACT: Introduction: The introduction of antibodies directed against tumour necrosis factor (anti-TNF) has dramatically changed the concept of treating patients with Crohn's disease (CD). Unfortunately, the long-term efficacy of anti-TNF agents may be hampered by immunogenicity. The availability of more anti-TNF agents in the therapeutic armamentarium would therefore be of great benefit in patients loosing response to another anti-TNF. In this review, the authors will focus on the efficacy of certolizumab pegol (CZP) . Areas covered: A literature search to January 2013 was performed to identify all trials studying CZP in patients with CD. The authors first focused on the mechanism of action of CZP. Second, they evaluated the efficacy of an induction and maintenance therapy with CZP and the impact of CZP on mucosal healing and fistula closure. Next, they explored the influence of previous anti-TNF exposure and baseline C-reactive protein levels. Finally, they analysed the safety data on CZP, including the development of antibodies against CZP and the use of CZP during pregnancy. Expert opinion: Based on the provided literature, CZP could be a good alternative in patients with moderate-to-severe CD failing another anti-TNF agent. More data are required to conclude on its impact on the long-term outcome of CD.
    Expert opinion on biological therapy 03/2013; · 3.22 Impact Factor
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    Journal of Crohn's and Colitis. 01/2013; 7(12):982–1018.
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    ABSTRACT: OBJECTIVES:Endoscopic mucosal healing is a key endpoint for the treatment of ulcerative colitis (UC). The role of microscopic activity in predicting disease relapse has not been fully assessed. We aimed to investigate the predictive role of serologic and histologic markers on disease relapse in UC patients with endoscopically inactive disease.METHODS:Adult UC patients with endoscopically inactive disease (Mayo 0) and a 12-month follow-up between 2008 and 2011 were retrospectively included. An expert pathologist evaluated all colonic biopsies for histologic activity (Geboes score) and the presence of basal plasmacytosis. Blood samples collected around the time of endoscopy were analyzed. Disease relapse, defined as a clinical Mayo score ≥3, was documented during follow-up.RESULTS:The study cohort consisted of 75 patients (53% men, median age 47 years). Despite normal endoscopy, histology showed inflammatory activity with a Geboes score ≥3.1 in 40% and basal plasmacytosis in 21% of patients. At 12 months, clinical relapse was observed in 20% (n=15) of patients. Presence of basal plasmacytosis (P=0.007) and a Geboes score ≥3.1 (P=0.007) were predictive of disease relapse. Using multivariate analysis, the presence of basal plasmacytosis was predictive of clinical relapse (odds ratio (OR) 5.13 (95% confidence interval (CI): 1.32-19.99), P=0.019), whereas the use of biologicals at endoscopy favored remission (OR 0.24 (95% CI: 0.05-1.01), P=0.052).CONCLUSIONS:We demonstrated that the presence of basal plasmacytosis predicts UC clinical relapse in patients with complete mucosal healing. We recommend closer follow-up and optimization of medical therapy in patients with basal plasmacytosis.Am J Gastroenterol advance online publication, 13 November 2012; doi:10.1038/ajg.2012.301.
    The American Journal of Gastroenterology 11/2012; · 7.55 Impact Factor
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    ABSTRACT: Interleukin-15 (IL-15) is a pro-inflammatory cytokine suspected to contribute to the inflammation in inflammatory bowel diseases (IBD). The specific receptor chain IL-15Rα can be expressed as a transmembranous signaling receptor, or can be cleaved by a disintegrin and metalloprotease domain 17 (ADAM17) into a neutralizing, soluble receptor (sIL-15Rα). The aim of this study is to evaluate the expression of IL-15Rα in ulcerative colitis (UC) and Crohn's disease (CD) patients before and after infliximab (IFX) therapy. Gene expression of IL-15Rα, IL-15 and ADAM17 was measured at the mRNA level by quantitative reverse transcriptase PCR in mucosal biopsies harvested before and after first IFX therapy. Concentrations of sIL-15Rα were measured in sera of patients by ELISA and IL-15Rα protein was localized in the gut by immunohistochemistry and immunofluorescence. Mucosal expression of IL-15Rα is increased in UC and CD patients as compared to controls and it remains elevated after IFX therapy in both responder and non-responder patients. The concentration of sIL-15Rα in serum is also increased in UC patients when compared to controls and does not differ between responders and non-responders both before and after IFX. CD patients have levels of sIL-15Rα comparable to healthy controls before and after therapy. In mucosal tissues, IL-15Rα+ cells closely resemble activated memory B cells with a preplasmablastic phenotype. To conclude, IBD patients have an increased expression of IL-15Rα mRNA in the mucosa. Expression is localized in B cells, suggesting that IL-15 regulates B cell functions during bowel inflammation. No change in release of sIL-15Rα is observed in patients treated with IFX. © 2012 The Authors. Immunology © 2012 Blackwell Publishing Ltd.
    Immunology 10/2012; · 3.71 Impact Factor

Publication Stats

2k Citations
418 Downloads
552.65 Total Impact Points

Institutions

  • 2013
    • McGill University Health Centre
      Montréal, Quebec, Canada
  • 2004–2013
    • Universitair Ziekenhuis Leuven
      • Department of Gastroenterology
      Leuven, VLG, Belgium
  • 2012
    • Academic Medical Center (AMC)
      Amsterdamo, North Holland, Netherlands
  • 2004–2012
    • Leuven University College
      Louvain, Flanders, Belgium
  • 2010
    • University of Otago
      Taieri, Otago Region, New Zealand