Abstract
Crohn's disease (CD) is a chronic immune-mediated disorder for which there is not a fully effective treatment. Moreover, biological therapy with anti-tumor necrosis factor-α (anti-TNF-α) monoclonal antibodies leads to an effective response in only 60–70% of patients. Our previous data suggested that specific loci polymorphism of the TNFRSF1B, FCGR3A, IL1R, IL1B, and FAS genes could be a predictor of the primary non-response to anti-TNF therapy in CD patients. In this work, we propose to explain this hypothesis by functional analysis in colon biopsies and in a cell culture model. Using the RT-qPCR analysis, we estimated the FCGR3A, IL1R, TNFRSF1B, IL1B, FAS, and ADAM17 genes mRNA level in colon biopsies material from inflamed and non-inflamed tissue from 21 CD patients (14 responders and 7 non-responders to anti-TNF therapy) and 6 controls, as well as in vitro in a peripheral blood mononuclear cells (PBMCs) from 14 CD patients (seven responders and seven non-responders to anti-TNF therapy) and eight controls cultured for 72 h with 10 μg/ml of anti-TNF antibody. Our findings demonstrated a significant down-regulation of TNFRSF1B gene expression in non-responders both in inflamed and in non-inflamed colon tissue, while the expression of the FCGR3A and IL1B genes was significantly up-regulated in non-responders in the inflamed colon region. In vitro research results indicate that the anti-TNF drug induced a significant decrease in TNFRSF1B, FCGR3A, and FAS gene expression in non-responders. These results show that altered TNFRSF1B, FCGR3A, and IL1B genes expression can be a predictor of the primary non-response to anti-TNF therapy in CD patients.
Highlights
Crohn’s disease (CD) is a type of inflammatory bowel disease (IBD), which generally affects the ileum and colon and is the result of an abnormal inflammatory response to antigens derived from the gastrointestinal tract [1]
In the research concerning the identification of molecular markers useful in predicting non-response to antiTNF biological agents, we described that polymorphism in apoptosis and inflammatory pathways genes could be associated with this phenomenon in CD patients [10]
The mRNA expression level of TNFRSF1B, FAS, FCGR3A, IL1B, IL1R, and ADAM17 genes was investigated to find potential differences between patients who did not respond to the therapy, patients who did respond, and healthy individuals
Summary
Crohn’s disease (CD) is a type of inflammatory bowel disease (IBD), which generally affects the ileum and colon and is the result of an abnormal inflammatory response to antigens derived from the gastrointestinal tract [1]. Its increased expression is found in both intestinal inflammatory infiltrates and in the serum of patients [2]. Anti-TNF Drug Effect in Crohn’s Disease involves the blockage of this cytokine has been increasingly used in the treatment of IBD [3]. With the use of anti-TNF-α drugs, it is possible to achieve clinical and endoscopic remission of the disease. There is a group of about one-third of IBD patients who primarily do not respond to this type of therapy. Despite the anti-TNF-α treatment, no clinical improvement or inhibition of the inflammatory process in the endoscopic image is observed [4, 5]
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