title: Dysregulation of innate immunity in ulcerative colitis patients who fail anti-tumor necrosis factor therapy.
abstract: OBJECTIVE
  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).
  
  
  CONCLUSIONS
  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.affiliation: Angela C Baird, Ian C Lawrance, Faculty of Medicine and Dentistry, School of Medicine and Pharmacology, University of Western Australia, Perth, WA 6009, Australia.
authors.forename: Angela C
authors.initials: AC
authors.lastname: Baird
authors.affiliation: Angela C Baird, Ian C Lawrance, Faculty of Medicine and Dentistry, School of Medicine and Pharmacology, University of Western Australia, Perth, WA 6009, Australia.
authors.forename: Dominic
authors.initials: D
authors.lastname: Mallon
authors.affiliation: Angela C Baird, Ian C Lawrance, Faculty of Medicine and Dentistry, School of Medicine and Pharmacology, University of Western Australia, Perth, WA 6009, Australia.
authors.forename: Graham
authors.initials: G
authors.lastname: Radford-Smith
authors.affiliation: Angela C Baird, Ian C Lawrance, Faculty of Medicine and Dentistry, School of Medicine and Pharmacology, University of Western Australia, Perth, WA 6009, Australia.
authors.forename: Julien
authors.initials: J
authors.lastname: Boyer
authors.affiliation: Angela C Baird, Ian C Lawrance, Faculty of Medicine and Dentistry, School of Medicine and Pharmacology, University of Western Australia, Perth, WA 6009, Australia.
authors.forename: Thierry
authors.initials: T
authors.lastname: Piche
authors.affiliation: Angela C Baird, Ian C Lawrance, Faculty of Medicine and Dentistry, School of Medicine and Pharmacology, University of Western Australia, Perth, WA 6009, Australia.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Prescott
authors.affiliation: Angela C Baird, Ian C Lawrance, Faculty of Medicine and Dentistry, School of Medicine and Pharmacology, University of Western Australia, Perth, WA 6009, Australia.
authors.forename: Ian C
authors.initials: IC
authors.lastname: Lawrance
authors.affiliation: Angela C Baird, Ian C Lawrance, Faculty of Medicine and Dentistry, School of Medicine and Pharmacology, University of Western Australia, Perth, WA 6009, Australia.
authors.forename: Meri K
authors.initials: MK
authors.lastname: Tulic
mesh_terms: D000293:Adolescent; D000328:Adult; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D001688:Biological Products / Q000627:therapeutic use*; D002478:Cells, Cultured; D002648:Child; D003093:Colitis, Ulcerative / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D005260:Female; D005765:Gastrointestinal Agents / Q000627:therapeutic use*; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000276:immunology / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012189:Retrospective Studies; D015398:Signal Transduction / Q000187:drug effects; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism; D017211:Treatment Failure; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000097:blood / Q000276:immunology; D055815:Young Adult
chemical_list: D000893:Anti-Inflammatory Agents; D001688:Biological Products; D005765:Gastrointestinal Agents; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; C507773:IRAK4 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases
keywords: Anti-tumor necrosis factor therapy; IRAK4; Inflammatory bowel disease; Innate immunity; Toll-like receptor; Ulcerative colitis