TY - JOUR

T1 - Associations between gastrointestinal toxicity, micro RNA and cytokine production in patients undergoing myeloablative allogeneic stem cell transplantation

AU - Pontoppidan, Peter Erik Lotko

AU - Jordan, Karina Kwi Im

AU - Carlsen, Anting Liu

AU - Uhlving, Hilde Hylland

AU - Kielsen, Katrine

AU - Christensen, Mette

AU - Ifversen, Marianne R Segelcke

AU - Nielsen, Claus Henrik

AU - Sangild, Per Torp

AU - Heegaard, Niels Henrik Helweg

AU - Heilmann, Carsten

AU - Sengeløv, Henrik

AU - Muller, Klaus

N1 - Copyright © 2015 Elsevier B.V. All rights reserved.

PY - 2015/3

Y1 - 2015/3

N2 - 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.

AB - 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.

KW - Adolescent

KW - Adult

KW - Biomarkers

KW - Cells, Cultured

KW - Child

KW - Child, Preschool

KW - Citrulline

KW - Cytokines

KW - Denmark

KW - Drug Therapy

KW - Enterocytes

KW - Gene Expression Regulation

KW - Hematopoietic Stem Cell Transplantation

KW - Humans

KW - Infant

KW - Inflammation Mediators

KW - Intestines

KW - Leukocytes, Mononuclear

KW - Lymphocyte Activation

KW - Male

KW - MicroRNAs

KW - Middle Aged

KW - Myeloablative Agonists

KW - Prospective Studies

KW - Transplantation Conditioning

KW - Young Adult

U2 - 10.1016/j.intimp.2014.12.038

DO - 10.1016/j.intimp.2014.12.038

M3 - Journal article

C2 - 25614225

VL - 25

SP - 180

EP - 188

JO - International Immunopharmacology

JF - International Immunopharmacology

SN - 1567-5769

IS - 1

ER -