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©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
Dysregulation of innate immunity in ulcerative colitis patients who fail anti-tumor necrosis factor therapy
Angela C Baird, Dominic Mallon, Graham Radford-Smith, Julien Boyer, Thierry Piche, Susan L Prescott, Ian C Lawrance, Meri K Tulic
Angela C Baird, Ian C Lawrance, Faculty of Medicine and Dentistry, School of Medicine and Pharmacology, University of Western Australia, Perth, WA 6009, Australia
Dominic Mallon, Department of Immunology, Fremantle Hospital, Perth, WA 6160, Australia
Graham Radford-Smith, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, 4006, Australia
Julien Boyer, Thierry Piche, Meri K Tulic, University of Nice Sophia-Antipolis, EA6302, 06202 Nice, France
Julien Boyer, Thierry Piche, Department of Gastroenterology and Nutrition, l’Archet Hospital 2, 06202 Nice, France
Susan L Prescott, School of Paediatrics and Child Health, University of Western Australia, Subiaco, WA 6008, Australia
Susan L Prescott, Meri K Tulic, International Inflammation network (in-FLAME) of the World Universities Network, University of Western Australia, Subiaco, WA 6008, Australia
Ian C Lawrance, Centre for Inflammatory Bowel Diseases, St John of God Subiaco Hospital, Perth, WA 6009, Australia
Meri K Tulic, Mediterranean Center for Molecular Medicine (C3M)-INSERM U1065, Team 12, 06204 Nice, France
Author contributions: Baird AC and Tulic MK were involved in data acquisition, analysis, interpretation of the data and writing of the manuscript; Baird AC, Mallon D, Radford-Smith G, Lawrance IC and Tulic MK were involved in study design; Prescott SL provided protocols and provision of laboratory space for some experiments; Boyer J, Piche T and Lawrance IC gave invaluable intellectual input into the study and clinical direction; Lawrance IC and Tulic MK proposed the original hypothesis of this study and approved the final version of this manuscript.
Institutional review board statement: The study was reviewed and approved by the Southern Metropolitan Health Service Human Ethics Committee and Institutional Review Board.
Informed consent statement: All biological samples from the patients were taken after informed consent.
Conflict-of-interest statement: To the best of our knowledge, there is no conflict of interest to declare.
Data sharing statement: Two senior co-authors (Lawrance IC and Tulic MK) have access to all data and dataset available from the corresponding author at meri.tulic@unice.fr.
Open-Access: 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. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Meri K Tulic, PhD, INSERM, CR1, Professor, Mediterranean Center for Molecular Medicine (C3M)-INSERM U1065, Team 12, Batiment Archimed, 151 route Saint-Antoine de Ginestiere, 06204 Nice, France. meri.tulic@unice.fr
Telephone: +33-4-89064326 Fax: +33-4-89064221
Received: July 8, 2016
Peer-review started: July 12, 2016
First decision: July 29, 2016
Revised: August 25, 2016
Accepted: September 28, 2016
Article in press: September 28, 2016
Published online: November 7, 2016
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.
Core tip: Anti-tumor necrosis factor (TNF) therapy is effective in approximately 60% of ulcerative colitis (UC) patients. Currently we do not know which patients are likely to benefit from this costly treatment. Here we show that differences in innate immune function [measured by patients response to toll-like-receptor (TLR), TLR agonists] exist between UC responders and non-responders. Differences exist in (1) content of immune and regulatory cells in their blood; (2) capacity of their cells to produce cytokines; and (3) in their signalling following TLR activation. Serological measure of TLR function may prove to be a useful tool in clinic to predict patient’s response to anti-TNF treatment.
