title: Thiopurine treatment in patients with Crohn's disease leads to a selective reduction of an effector cytotoxic gene expression signature revealed by whole-genome expression profiling.
abstract: Crohn's disease (CD) is characterized by chronic inflammation of the gastrointestinal tract, as a result of aberrant activation of the innate immune system through TLR stimulation by bacterial products. The conventional immunosuppressive thiopurine derivatives (azathioprine and mercaptopurine) are used to treat CD. The effects of thiopurines on circulating immune cells and TLR responsiveness are unknown. To obtain a global view of affected gene expression of the immune system in CD patients and the treatment effect of thiopurine derivatives, we performed genome-wide transcriptome analysis on whole blood samples from 20 CD patients in remission, of which 10 patients received thiopurine treatment, compared to 16 healthy controls, before and after TLR4 stimulation with LPS. Several immune abnormalities were observed, including increased baseline interferon activity, while baseline expression of ribosomal genes was reduced. After LPS stimulation, CD patients showed reduced cytokine and chemokine expression. None of these effects were related to treatment. Strikingly, only one highly correlated set of 69 genes was affected by treatment, not influenced by LPS stimulation and consisted of genes reminiscent of effector cytotoxic NK cells. The most reduced cytotoxicity-related gene in CD was the cell surface marker CD160. Concordantly, we could demonstrate an in vivo reduction of circulating CD160(+)CD3(-)CD8(-) cells in CD patients after treatment with thiopurine derivatives in an independent cohort. In conclusion, using genome-wide profiling, we identified a disturbed immune activation status in peripheral blood cells from CD patients and a clear treatment effect of thiopurine derivatives selectively affecting effector cytotoxic CD160-positive cells.
authors: VU University Medical Center, Deptartment of Gastroenterology, Amsterdam, The Netherlands.
authors: G
authors: G
authors: Bouma
authors: J M
authors: JM
authors: Baggen
authors: A A
authors: AA
authors: van Bodegraven
authors: C J J
authors: CJ
authors: Mulder
authors: G
authors: G
authors: Kraal
authors: A
authors: A
authors: Zwiers
authors: A J
authors: AJ
authors: Horrevoets
authors: C T M
authors: CT
authors: van der Pouw Kraan
mesh_terms: D000328:Adult; D015703:Antigens, CD / Q000097:blood / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D001379:Azathioprine / Q000627:therapeutic use*; D002478:Cells, Cultured; D018925:Chemokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003424:Crohn Disease / Q000097:blood / Q000188:drug therapy* / Q000235:genetics* / Q000276:immunology; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D007372:Interferons / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008297:Male; D015122:Mercaptopurine / Q000627:therapeutic use*; D012270:Ribosomes / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D059467:Transcriptome / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D015703:Antigens, CD; D018925:Chemokines; D008070:Lipopolysaccharides; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D014157:Transcription Factors; D007372:Interferons; D015122:Mercaptopurine; D001379:Azathioprine