Reduction of CD68+ Macrophages and Decreased IL-17 Expression in Intestinal Mucosa of Patients with Inflammatory Bowel Disease Strongly Correlate With Endoscopic Response and Mucosal Healing following Infliximab Therapy

Caprioli, Flavio; Bosè, Francesca; Rossi, Riccardo L.; Petti, Luciana; Viganò, Chiara; Ciafardini, C.; Raeli, Lorenzo; Basilisco, Guido; Ferrero, Stefano; Pagani, Massimiliano; Conte, Dario; Gf, Altomare; Monteleone, Giovanni; Abrignani, Sergio; Reali, Eva

doi:10.1097/mib.0b013e318280292b

Cited by 65 publications

(49 citation statements)

References 31 publications

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“…Although there are no data available whether IBD patients non-responding to IFX therapy are at an increased risk for colon cancer, an animal study indicated that IBD animals treated with IFX are protected from colon cancer [22][23][24][25][26][27][28][29]. Therefore, one may also speculate that patients having high Wnt5a gene expression may be subjected to IFX non-responsiveness and, also, are at a higher risk of cancer.…”

Section: Discussionmentioning

confidence: 97%

Validation of Biomarkers in Gene Expression Datasets of Inflammatory Bowel Disease: IL13RA2, PTGS2 and WNT5A as Predictors of Responsiveness to Infliximab Therapy

Győrffy¹

2014

J Proteomics Bioinform

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Background: Some patients with inflammatory bowel disease (IBD) do not respond to infliximab (IFX) therapy. Gene expression studies revealed genes that may help to predict non-responding IBD patients. Our purpose was to validate the discriminating power of published genes. Methods:Microarray datasets of IBD patients responding or non-responding to IFX were downloaded from GEO database ('transcriptomic arm'). Published genes discriminating responding and non-responding patients were identified in PubMed ('biomarker arm'). Using ROC-analysis, the discriminating performance of genes in 'biomarker arm' were re-tested in each datasets of 'transcriptomic arm'. We also performed an independent analysis of colon biopsy datasets to identify novel discriminating genes. Results:The transcriptomic arm of four GEO datasets (3 and 1 from colon biopsies and blood cells, respectively) included 99 patients (of those, 59 and 40 were IFX responder and non-responder, respectively). Of the 65 candidate genes reported in biopsy specimens 25 genes discriminated significantly (p<0.05) infliximab responders and nonresponders in the three biopsy datasets consistently. Of the 39 candidate genes reported in peripheral blood 9 genes provided significant discrimination after re-testing. Independent analysis of three biopsy datasets identified the top five genes. Three genes (IL13RA2, PTGS2 and WNT5A) were highly effective discriminator in each analysis. Conclusion:This analysis identified IL13RA2, PTGS2 and WNT5A, three genes in colonic tissues of IBD patients as suitable to discrimination between patients responding and non-responding to IFX therapy. These genes encode proteins implicated in intestinal pathology; the high expression in non-responding patients may indicate important targets in IBD therapy.

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Section: Discussionmentioning

confidence: 97%

Validation of Biomarkers in Gene Expression Datasets of Inflammatory Bowel Disease: IL13RA2, PTGS2 and WNT5A as Predictors of Responsiveness to Infliximab Therapy

Győrffy¹

2014

J Proteomics Bioinform

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“…Also, clinical studies support the role of Th17 in the pathogenesis of IBD. Infliximab, a monoclonal antibody against tumor necrosis factor (TNF), alleviates IBD-related mucosal inflammation via downregulation of IL-17A expression [57]. Aside from accumulating evidence for a crucial role of Th17 cells in IBD, clinical data also connects IBD to AIP.…”

Section: Discussionmentioning

confidence: 98%

Potential role of Th17 cells in the pathogenesis of type 2 autoimmune pancreatitis

et al. 2015

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Th17 cells have been shown to play an important role in the pathogenesis of a variety of autoimmune diseases. The aim of this study was to investigate the potential role of Th17 cells in autoimmune pancreatitis (AIP). Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to determine gene expression of the signature cytokines of Th17 cells IL-17A and IL-21 and of the Th17 lineage-specific transcription factor retinoic acid receptor-related orphan receptor C (RORC) in human tissue specimens of AIP, classical chronic pancreatitis (CP), and normal pancreas (NP). Infiltrating immune cells were characterized by immunohistochemistry (IHC). Gene expression of IL-17A, IL-21, and RORC were found to be significantly increased in AIP. Accordingly, the number of Th17 cells was significantly increased in AIP compared to NP or CP. Both gene expression analysis and IHC revealed a clear difference between type 1 and 2 AIP. In the periductal compartment of type 2 AIP, which is characterized by granulocytic epithelial lesions (GELs), the number of infiltrating Th17 cells and neutrophilic granulocytes was significantly increased compared to type 1 AIP. Our data suggest that Th17 cells play a role in the pathogenesis of AIP, in particular of type 2 AIP. Cross-talk between Th17 cells and neutrophilic granulocytes mediated via IL-17A may be a potential mechanism by which neutrophils are recruited to the duct and acinar cells with subsequent destruction, a process that is pathognomonic for type 2 AIP.

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“…It is believed that one of the crucial phenomena leading to the down-regulation of inflammatory infiltration in the intestinal tissue is the induction of apoptosis of immune cells [1][2][3]. Study from our group showed that the proportion of apoptotic lamina propria mononuclear cells (LPMC) is increased after anti-TNF therapy, as evidenced in mucosal biopsies taken from inflamed areas of the colon in patients with CD [4].…”

Section: Introductionmentioning

confidence: 76%

Anti-TNF antibodies do not induce the apoptosis of lamina propria mononuclear cells in uninflamed intestinal tissue in patients with Crohn’s disease

Eder

Łykowska‐Szuber

Krela‐Kaźmierczak

et al. 2013

Folia Histochem Cytobiol.

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Abstract:It is not known if anti-tumor necrosis factor (anti-TNF) agents provoke only apoptosis of lamina propria mononuclear cells (LPMC) engaged in inflammatory processes or whether it's a general phenomenon concerning all LPMC. In this study we carried out an immunohistochemical analysis of the expression of several apoptosis-related proteins (active caspase-3, Bax, Bcl-2, Fas, TNFR1, CD4, and CD8) in uninflamed mucosa in Crohn's disease (CD) patients treated with anti-TNF agents. 16 CD patients (mean age 34 ± 11, mean disease duration 7 ± 5 years) were included in the study. 10 patients were treated with infliximab and 6 -with adalimumab. The expression of active caspase 3, Bax, Bcl-2, Fas, TNFR1 and CD8 in LPMC did not change significantly after the therapy. We concluded that anti-TNF antibodies did not promote LPMC apoptosis in uninflamed tissues. This is in contrast to the phenomena observed in inflamed tissues. These data show that anti-TNF antibodies rather restore the susceptibility to apoptosis of LPMC in inflamed areas of the gut in CD, than directly induce LPMC apoptosis; otherwise the anti-TNF antibodies should have also induced apoptosis in the uninflamed mucosa.

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Reduction of CD68+ Macrophages and Decreased IL-17 Expression in Intestinal Mucosa of Patients with Inflammatory Bowel Disease Strongly Correlate With Endoscopic Response and Mucosal Healing following Infliximab Therapy

Cited by 65 publications

References 31 publications

Validation of Biomarkers in Gene Expression Datasets of Inflammatory Bowel Disease: IL13RA2, PTGS2 and WNT5A as Predictors of Responsiveness to Infliximab Therapy

Validation of Biomarkers in Gene Expression Datasets of Inflammatory Bowel Disease: IL13RA2, PTGS2 and WNT5A as Predictors of Responsiveness to Infliximab Therapy

Potential role of Th17 cells in the pathogenesis of type 2 autoimmune pancreatitis

Anti-TNF antibodies do not induce the apoptosis of lamina propria mononuclear cells in uninflamed intestinal tissue in patients with Crohn’s disease

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