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Dysregulation of innate immunity in ulcerative colitis patients who fail anti-tumor necrosis factor therapy.
World J Gastroenterol. 2016 Nov 07; 22(41):9104-9116.WJ

Abstract

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.

Authors+Show Affiliations

Angela C Baird, Ian C Lawrance, Faculty of Medicine and Dentistry, School of Medicine and Pharmacology, University of Western Australia, Perth, WA 6009, Australia.Angela C Baird, Ian C Lawrance, Faculty of Medicine and Dentistry, School of Medicine and Pharmacology, University of Western Australia, Perth, WA 6009, Australia.Angela C Baird, Ian C Lawrance, Faculty of Medicine and Dentistry, School of Medicine and Pharmacology, University of Western Australia, Perth, WA 6009, Australia.Angela C Baird, Ian C Lawrance, Faculty of Medicine and Dentistry, School of Medicine and Pharmacology, University of Western Australia, Perth, WA 6009, Australia.Angela C Baird, Ian C Lawrance, Faculty of Medicine and Dentistry, School of Medicine and Pharmacology, University of Western Australia, Perth, WA 6009, Australia.Angela C Baird, Ian C Lawrance, Faculty of Medicine and Dentistry, School of Medicine and Pharmacology, University of Western Australia, Perth, WA 6009, Australia.Angela C Baird, Ian C Lawrance, Faculty of Medicine and Dentistry, School of Medicine and Pharmacology, University of Western Australia, Perth, WA 6009, Australia.Angela C Baird, Ian C Lawrance, Faculty of Medicine and Dentistry, School of Medicine and Pharmacology, University of Western Australia, Perth, WA 6009, Australia.

Pub Type(s)

Journal Article
Observational Study

Language

eng

PubMed ID

27895398

Citation

Baird, Angela C., et al. "Dysregulation of Innate Immunity in Ulcerative Colitis Patients Who Fail Anti-tumor Necrosis Factor Therapy." World Journal of Gastroenterology, vol. 22, no. 41, 2016, pp. 9104-9116.
Baird AC, Mallon D, Radford-Smith G, et al. Dysregulation of innate immunity in ulcerative colitis patients who fail anti-tumor necrosis factor therapy. World J Gastroenterol. 2016;22(41):9104-9116.
Baird, A. C., Mallon, D., Radford-Smith, G., Boyer, J., Piche, T., Prescott, S. L., Lawrance, I. C., & Tulic, M. K. (2016). Dysregulation of innate immunity in ulcerative colitis patients who fail anti-tumor necrosis factor therapy. World Journal of Gastroenterology, 22(41), 9104-9116.
Baird AC, et al. Dysregulation of Innate Immunity in Ulcerative Colitis Patients Who Fail Anti-tumor Necrosis Factor Therapy. World J Gastroenterol. 2016 Nov 7;22(41):9104-9116. PubMed PMID: 27895398.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Dysregulation of innate immunity in ulcerative colitis patients who fail anti-tumor necrosis factor therapy. AU - Baird,Angela C, AU - Mallon,Dominic, AU - Radford-Smith,Graham, AU - Boyer,Julien, AU - Piche,Thierry, AU - Prescott,Susan L, AU - Lawrance,Ian C, AU - Tulic,Meri K, PY - 2016/07/08/received PY - 2016/08/25/revised PY - 2016/09/28/accepted PY - 2016/11/30/entrez PY - 2016/11/30/pubmed PY - 2017/4/25/medline KW - Anti-tumor necrosis factor therapy KW - IRAK4 KW - Inflammatory bowel disease KW - Innate immunity KW - Toll-like receptor KW - Ulcerative colitis SP - 9104 EP - 9116 JF - World journal of gastroenterology JO - World J. Gastroenterol. VL - 22 IS - 41 N2 - 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. SN - 2219-2840 UR - https://www.unboundmedicine.com/medline/citation/27895398/Dysregulation_of_innate_immunity_in_ulcerative_colitis_patients_who_fail_anti_tumor_necrosis_factor_therapy_ L2 - http://www.wjgnet.com/1007-9327/full/v22/i41/9104.htm DB - PRIME DP - Unbound Medicine ER -