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Monocytes from infliximab-resistant patients with Crohn's disease exhibit a disordered cytokine profile.

ABSTRACT: Crohn's disease (CD) is a chronic inflammatory disorder characterized by immune response dysregulation. Tumor necrosis factor-? (TNF?) is a key cytokine in the pathogenesis of CD, as indicated by the efficacy of anti-TNF-? therapy with infliximab (IFX). However, approximately 30-40% of CD patients fail to respond to IFX with still unclear underlying mechanisms. This study compares the inflammatory phenotype of monocytes from CD patients, who respond or non-respond to IFX. Under basal conditions, the mRNA for the cytokines TNF?, IL-23, IL-1? and the chemokines CXCL8/IL-8, CCL5/RANTES and CCL2/MCP-1 was up-regulated in monocytes from non-responders than responders. The expression of the same cytokines and CCL2/MCP-1 was higher in non-responders also upon LPS treatment. Moreover, higher secretion of TNF?, IL-1?, IFN? and IL-2 proteins occurred in the supernatants of LPS-treated non-responders cells. Resistance to IFX in CD may result from a transcriptional dysregulation of circulating monocytes, leading to hyperactivation of pro-inflammatory pathways. Monocytes' cytokine profile may thus represent a predictive marker of response to IFX. Monocytes were isolated from blood samples of 19 CD patients (11 responders, 8 non-responders) and incubated with or without LPS. Cytokine profiles were assessed by RT-qPCR and, in the supernatants, by ELISA assay.

SUBMITTER: Gaiani F

PROVIDER: S-EPMC7376177 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Monocytes from infliximab-resistant patients with Crohn's disease exhibit a disordered cytokine profile.

Gaiani Federica F Rotoli Bianca Maria BM Ferrari Francesca F Barilli Amelia A Visigalli Rossana R Carra Maria Clotilde MC de'Angelis Gian Luigi GL de'Angelis Nicola N Dall'Asta Valeria V

Scientific reports 20200722 1

Crohn's disease (CD) is a chronic inflammatory disorder characterized by immune response dysregulation. Tumor necrosis factor-α (TNFα) is a key cytokine in the pathogenesis of CD, as indicated by the efficacy of anti-TNF-α therapy with infliximab (IFX). However, approximately 30-40% of CD patients fail to respond to IFX with still unclear underlying mechanisms. This study compares the inflammatory phenotype of monocytes from CD patients, who respond or non-respond to IFX. Under basal conditions, ...[more]

PMID: 32699266

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Project description:PurposeTo develop a CT-based radiomics model combining with VAT and bowel features to improve the predictive efficacy of IFX therapy on the basis of bowel model.MethodsThis retrospective study included 231 CD patients (training cohort, n = 112; internal validation cohort, n = 48; external validation cohort, n = 71) from two tertiary centers. Machine-learning VAT model and bowel model were developed separately to identify CD patients with primary nonresponse to IFX. A comprehensive model incorporating VAT and bowel radiomics features was further established to verify whether CT features extracted from VAT would improve the predictive efficacy of bowel model. Area under the curve (AUC) and decision curve analysis were used to compare the prediction performance. Clinical utility was assessed by integrated differentiation improvement (IDI).ResultsVAT model and bowel model exhibited comparable performance for identifying patients with primary nonresponse in both internal (AUC: VAT model vs bowel model, 0.737 (95% CI, 0.590-0.854) vs. 0.832 (95% CI, 0.750-0.896)) and external validation cohort [AUC: VAT model vs. bowel model, 0.714 (95% CI, 0.595-0.815) vs. 0.799 (95% CI, 0.687-0.885)), exhibiting a relatively good net benefit. The comprehensive model incorporating VAT into bowel model yielded a satisfactory predictive efficacy in both internal (AUC, 0.840 (95% CI, 0.706-0.930)) and external validation cohort (AUC, 0.833 (95% CI, 0.726-0.911)), significantly better than bowel alone (IDI = 4.2% and 3.7% in internal and external validation cohorts, both p < 0.05).ConclusionVAT has an effect on IFX treatment response. It improves the performance for identification of CD patients at high risk of primary nonresponse to IFX therapy with selected features from RM.Critical relevance statementOur radiomics model (RM) for VAT-bowel analysis captured the pathophysiological changes occurring in VAT and whole bowel lesion, which could help to identify CD patients who would not response to infliximab at the beginning of therapy.Key points• Radiomics signatures with VAT and bowel alone or in combination predicting infliximab efficacy. • VAT features contribute to the prediction of IFX treatment efficacy. • Comprehensive model improved the performance compared with the bowel model alone.

Dataset Information

Monocytes from infliximab-resistant patients with Crohn's disease exhibit a disordered cytokine profile.

Publications

Monocytes from infliximab-resistant patients with Crohn's disease exhibit a disordered cytokine profile.

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