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This study suggests a probable association of the Fok I polymorphism in VDR receptor gene and Crohn's susceptibility in Iranian population.

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Objectives:Anti-tumor necrosis factor (TNF)-α agents like Infliximab (IFX) are effective in the treatment of inflammatory bowel diseases (IBDs) and are widely used. However, a considerable number of patients do not respond or lose response to this therapy. Preliminary evidence suggests that transmembrane TNF-α (tmTNF-α) might be linked to response to IFX by promoting reverse signaling-induced apoptosis in inflammatory cells. The main aim of this study was the evaluation of this hypothesis in primary IFX non-responders.Methods:A total of 47 IFX naive IBD patients were included in the study. Blood samples were taken before the start of IFX therapy (at week 0) and after induction therapy (at week 14). Endoscopic disease activity and markers of inflammation at baseline and at week 14 were used to evaluate response. Baseline soluble TNF-α (sTNF-α), percentage of circulating TNF-α positive cells, mean fluorescence intensity (MFI) of tmTNF-α, and apoptosis rate at week 14 in the peripheral blood mononuclear cells (PBMCs) were evaluated in IFX responders and non-responders.Results:Mean sTNF-α was not significantly different in responders compared to non-responders (P=0.13). Mean percentage of tmTNF-α bearing lymphocytes and monocytes was higher in the PBMCs of responders (P=0.05 and P=0.014, respectively). Mean MFI of tmTNF-α in circulating lymphocytes and monocytes was greater in responders (P=0.002 and P<0.001, respectively). Moreover, the mean percentage of apoptosis in PBMCs was significantly greater in responders compared to non-responders (P=0.002).Conclusions:The percentage of tmTNF-α bearing lymphocytes and monocytes and the intensity of tmTNF-α in the circulating leukocyte population of IBD patients was directly related to primary response to IFX. This was likely due—as assessed by the apoptosis rate—to promotion of inflammatory cell death. Thus, our data suggest that peripheral leukocytes could in principle be used for predicting primary response to IFX in IBD patients.

In inflammatory bowel diseases (IBD), the therapeutic benefit and mucosal healing from specific probiotics may relate to the modulation of dendritic cells (DCs). Herein, we assessed the immunomodulatory effects of four probiotic strains including Lactobacillus salivarius, Bifidobacterium bifidum, Bacillus coagulans and Bacillus subtilis natto on the expression of co-stimulatory molecules, cytokine production and gene expression of signal-transducing receptors in DCs from IBD patients. Human monocyte-derived DCs from IBD patients and healthy controls were exposed to four probiotic strains. The expression of co-stimulatory molecules was assessed and supernatants were analyzed for anti-inflammatory cytokines. The gene expression of toll-like receptors (TLRs), IL-12p40 and integrin αvβ8 were also analyzed. CD80 and CD86 were induced by most probiotic strains in ulcerative colitis (UC) patients whereas only B. bifidum induced CD80 and CD86 expression in Crohn’s disease (CD) patients. IL-10 and TGF-β production was increased in a dose-independent manner while TLR expression was decreased by all probiotic bacteria except B. bifidum in DCs from UC patients. TLR-4 and TLR-9 expression was significantly downregulated while integrin ß8 was significantly increased in the DCs from CD patients. IL-12p40 expression was only significantly downregulated in DCs from CD patients. Our findings point to the general beneficial effects of probiotics in DC immunomodulation and indicate that probiotic bacteria favorably modulate the expression of co-stimulatory molecules, proinflammatory cytokines and TLRs in DCs from IBD patients.