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Dysregulation of innate immunity in ulcerative colitis patients who fail anti-tumor necrosis factor therapy

AIM: To study the innate immune function in ulcerative colitis (UC) patients who fail to respond to anti-tumor necrosis factor (TNF) therapy. METHODS: Effects of anti-TNF therapy, inflammation and medications on innate immune function were assessed by measuring peripheral blood mononuclear cell (PBM...

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Autores principales: Baird, Angela C, Mallon, Dominic, Radford-Smith, Graham, Boyer, Julien, Piche, Thierry, Prescott, Susan L, Lawrance, Ian C, Tulic, Meri K
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Baishideng Publishing Group Inc 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5107592/
https://www.ncbi.nlm.nih.gov/pubmed/27895398
http://dx.doi.org/10.3748/wjg.v22.i41.9104
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author Baird, Angela C
Mallon, Dominic
Radford-Smith, Graham
Boyer, Julien
Piche, Thierry
Prescott, Susan L
Lawrance, Ian C
Tulic, Meri K
author_facet Baird, Angela C
Mallon, Dominic
Radford-Smith, Graham
Boyer, Julien
Piche, Thierry
Prescott, Susan L
Lawrance, Ian C
Tulic, Meri K
author_sort Baird, Angela C
collection PubMed
description AIM: To study the innate immune function in ulcerative colitis (UC) patients who fail to respond to anti-tumor necrosis factor (TNF) therapy. METHODS: Effects of anti-TNF therapy, inflammation and medications on innate immune function were assessed by measuring peripheral blood mononuclear cell (PBMC) cytokine expression from 18 inflammatory bowel disease patients pre- and 3 mo post-anti-TNF therapy. Toll-like receptor (TLR) expression and cytokine production post TLR stimulation was assessed in UC “responders” (n = 12) and “non-responders” (n = 12) and compared to healthy controls (n = 12). Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels were measured in blood to assess disease severity/activity and inflammation. Pro-inflammatory (TNF, IL-1β, IL-6), immuno-regulatory (IL-10), Th1 (IL-12, IFNγ) and Th2 (IL-9, IL-13, IL-17A) cytokine expression was measured with enzyme-linked immunosorbent assay while TLR cellular composition and intracellular signalling was assessed with FACS. RESULTS: Prior to anti-TNF therapy, responders and non-responders had similar level of disease severity and activity. PBMC’s ability to respond to TLR stimulation was not affected by TNF therapy, patient’s severity of the disease and inflammation or their medication use. At baseline, non-responders had elevated innate but not adaptive immune responses compared to responders (P < 0.05). Following TLR stimulation, non-responders had consistently reduced innate cytokine responses to all TLRs compared to healthy controls (P < 0.01) and diminished TNF (P < 0.001) and IL-1β (P < 0.01) production compared to responders. This innate immune dysfunction was associated with reduced number of circulating plasmacytoid dendritic cells (pDCs) (P < 0.01) but increased number of CD4+ regulatory T cells (Tregs) (P = 0.03) as well as intracellular accumulation of IRAK4 in non-responders following TLR-2, -4 and -7 activation (P < 0.001). CONCLUSION: Reduced innate immunity in non-responders may explain reduced efficacy to anti-TNF therapy. These serological markers may prove useful in predicting the outcome of costly anti-TNF therapy.
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spelling pubmed-51075922016-11-28 Dysregulation of innate immunity in ulcerative colitis patients who fail anti-tumor necrosis factor therapy Baird, Angela C Mallon, Dominic Radford-Smith, Graham Boyer, Julien Piche, Thierry Prescott, Susan L Lawrance, Ian C Tulic, Meri K World J Gastroenterol Basic Study AIM: To study the innate immune function in ulcerative colitis (UC) patients who fail to respond to anti-tumor necrosis factor (TNF) therapy. METHODS: Effects of anti-TNF therapy, inflammation and medications on innate immune function were assessed by measuring peripheral blood mononuclear cell (PBMC) cytokine expression from 18 inflammatory bowel disease patients pre- and 3 mo post-anti-TNF therapy. Toll-like receptor (TLR) expression and cytokine production post TLR stimulation was assessed in UC “responders” (n = 12) and “non-responders” (n = 12) and compared to healthy controls (n = 12). Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels were measured in blood to assess disease severity/activity and inflammation. Pro-inflammatory (TNF, IL-1β, IL-6), immuno-regulatory (IL-10), Th1 (IL-12, IFNγ) and Th2 (IL-9, IL-13, IL-17A) cytokine expression was measured with enzyme-linked immunosorbent assay while TLR cellular composition and intracellular signalling was assessed with FACS. RESULTS: Prior to anti-TNF therapy, responders and non-responders had similar level of disease severity and activity. PBMC’s ability to respond to TLR stimulation was not affected by TNF therapy, patient’s severity of the disease and inflammation or their medication use. At baseline, non-responders had elevated innate but not adaptive immune responses compared to responders (P < 0.05). Following TLR stimulation, non-responders had consistently reduced innate cytokine responses to all TLRs compared to healthy controls (P < 0.01) and diminished TNF (P < 0.001) and IL-1β (P < 0.01) production compared to responders. This innate immune dysfunction was associated with reduced number of circulating plasmacytoid dendritic cells (pDCs) (P < 0.01) but increased number of CD4+ regulatory T cells (Tregs) (P = 0.03) as well as intracellular accumulation of IRAK4 in non-responders following TLR-2, -4 and -7 activation (P < 0.001). CONCLUSION: Reduced innate immunity in non-responders may explain reduced efficacy to anti-TNF therapy. These serological markers may prove useful in predicting the outcome of costly anti-TNF therapy. Baishideng Publishing Group Inc 2016-11-07 2016-11-07 /pmc/articles/PMC5107592/ /pubmed/27895398 http://dx.doi.org/10.3748/wjg.v22.i41.9104 Text en ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved. http://creativecommons.org/licenses/by-nc/4.0/ This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.
spellingShingle Basic Study
Baird, Angela C
Mallon, Dominic
Radford-Smith, Graham
Boyer, Julien
Piche, Thierry
Prescott, Susan L
Lawrance, Ian C
Tulic, Meri K
Dysregulation of innate immunity in ulcerative colitis patients who fail anti-tumor necrosis factor therapy
title Dysregulation of innate immunity in ulcerative colitis patients who fail anti-tumor necrosis factor therapy
title_full Dysregulation of innate immunity in ulcerative colitis patients who fail anti-tumor necrosis factor therapy
title_fullStr Dysregulation of innate immunity in ulcerative colitis patients who fail anti-tumor necrosis factor therapy
title_full_unstemmed Dysregulation of innate immunity in ulcerative colitis patients who fail anti-tumor necrosis factor therapy
title_short Dysregulation of innate immunity in ulcerative colitis patients who fail anti-tumor necrosis factor therapy
title_sort dysregulation of innate immunity in ulcerative colitis patients who fail anti-tumor necrosis factor therapy
topic Basic Study
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5107592/
https://www.ncbi.nlm.nih.gov/pubmed/27895398
http://dx.doi.org/10.3748/wjg.v22.i41.9104
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