title: Associations between gastrointestinal toxicity, micro RNA and cytokine production in patients undergoing myeloablative allogeneic stem cell transplantation.
abstract: Allogeneic hematopoietic stem cell transplantation (HSCT) is a procedure with a high risk of treatment related mortality. The primary aim of the present study was to examine associations between markers of gastrointestinal toxicity, markers of systemic inflammation, and plasma levels of microRNA (miRNA) -155 and -146a during the first month after HSCT. The secondary aim was to characterize the impact of the toxic-inflammatory response on the function of circulating leukocytes during immune recovery. Thirty HSCT patients were included. Gastrointestinal injury was monitored by toxicity scores, lactulose-mannitol test and plasma citrulline, as a measure of the enterocyte population. Nadir of citrulline and maximum of oral toxicity scores, intestinal permeability, CRP and plasma levels of IL-6 and IL-10 was seen at day +7 post-HSCT. miRNA-155 and mi-RNA-146a showed an inverse relation with significantly elevated miRNA-155 and decreased miRNA-146a levels, from day 0 to day +28 compared with pre-conditioning levels. Citrulline levels below the median at day +7 were associated with higher spontaneous production of IL-6 and TNF-α as well as higher in vitro stimulated production of IL-17A at day +21. This study is the first to demonstrate that toxic responses to chemotherapy are accompanied by differential regulation of miRNAs with opposing effects on immune regulation. We find that a proinflammatory miRNA profile is sustained during the first three weeks after the transplantation, indicating that these miRNAs may play a role in the regulation of the inflammatory environment during immune reconstitution after HSCT.
authors.affiliation: Rigshospitalet, Copenhagen, Denmark; Department of Nutrition, Exercise and Sports, University of Copenhagen, Denmark. Electronic address: p.pontoppidan@dadlnet.dk.
authors.forename: Peter L
authors.initials: PL
authors.lastname: Pontoppidan
authors.affiliation: Rigshospitalet, Copenhagen, Denmark; Institute for Inflammation Research, Department of Infectious Diseases and Rheumatology, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Karina
authors.initials: K
authors.lastname: Jordan
authors.affiliation: Department of Clinical Biochemistry, Immunology and Genetics, Statens Serum Institut, Denmark.
authors.forename: Anting Liu
authors.initials: AL
authors.lastname: Carlsen
authors.affiliation: Rigshospitalet, Copenhagen, Denmark; Institute for Inflammation Research, Department of Infectious Diseases and Rheumatology, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Hilde Hylland
authors.initials: HH
authors.lastname: Uhlving
authors.affiliation: Rigshospitalet, Copenhagen, Denmark; Institute for Inflammation Research, Department of Infectious Diseases and Rheumatology, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Katrine
authors.initials: K
authors.lastname: Kielsen
authors.affiliation: Department of Clinical Genetics, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Mette
authors.initials: M
authors.lastname: Christensen
authors.affiliation: Rigshospitalet, Copenhagen, Denmark.
authors.forename: Marianne
authors.initials: M
authors.lastname: Ifversen
authors.affiliation: Institute for Inflammation Research, Department of Infectious Diseases and Rheumatology, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Claus Henrik
authors.initials: CH
authors.lastname: Nielsen
authors.affiliation: Rigshospitalet, Copenhagen, Denmark; Department of Nutrition, Exercise and Sports, University of Copenhagen, Denmark.
authors.forename: Per
authors.initials: P
authors.lastname: Sangild
authors.affiliation: Department of Clinical Biochemistry, Immunology and Genetics, Statens Serum Institut, Denmark; Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Denmark.
authors.forename: Niels Henrik Helweg
authors.initials: NH
authors.lastname: Heegaard
authors.affiliation: Rigshospitalet, Copenhagen, Denmark.
authors.forename: Carsten
authors.initials: C
authors.lastname: Heilmann
authors.affiliation: Department Haematology, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Henrik
authors.initials: H
authors.lastname: Sengeløv
authors.affiliation: Rigshospitalet, Copenhagen, Denmark; Institute for Inflammation Research, Department of Infectious Diseases and Rheumatology, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Klaus
authors.initials: K
authors.lastname: Müller
mesh_terms: D000293:Adolescent; D000328:Adult; D015415:Biomarkers / Q000378:metabolism; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D002956:Citrulline / Q000097:blood; D016207:Cytokines / Q000097:blood; D003718:Denmark; D004358:Drug Therapy; D020895:Enterocytes / Q000187:drug effects* / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D018836:Inflammation Mediators / Q000097:blood; D007422:Intestines / Q000473:pathology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008875:Middle Aged; D019653:Myeloablative Agonists / Q000627:therapeutic use*; D011446:Prospective Studies; D019172:Transplantation Conditioning / Q000379:methods*; D055815:Young Adult
chemical_list: D015415:Biomarkers; D016207:Cytokines; D018836:Inflammation Mediators; C542542:MIRN146 microRNA, human; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; D019653:Myeloablative Agonists; D002956:Citrulline
keywords: Citrulline; Cytokines; Gastrointestinal toxicity; HSCT; Micro-RNA