Telomere shortening in enterocytes of patients with uncontrolled acute intestinal graft-versus-host disease.
Acute intestinal graft-versus-host disease (aGVHD) refractory to immunosuppressive treatment is a serious complication after allogenic hematopoietic stem cell transplantation (HSCT). The underlying mechanisms of refractory aGVHD of the gut are not fully understood. Although telomere length (TL) reflects the replicative history of a cell, critically short telomeres have been associated with replicative exhaustion and tissue failure. In this study, we demonstrate that enterocytes of patients with refractory intestinal aGVHD show significantly increased proliferation, which translates into significant and critical telomere attrition following HSCT as compared with unaffected patients undergoing HSCT. Calculated telomere loss in aGVHD patients is 190 bp/wk, thereby massively exceeding physiological steady-state TL shortening rates such as in lymphocytes (∼50 bp/y). Our data support the hypothesis that increased compensatory proliferation following continued tissue damage can result in massive telomere loss in enterocytes of aGVHD patients. The present study introduces aGVHD-triggered increased cellular turnover and telomere loss with subsequent replicative exhaustion as a mechanism for refractory gut GVHD that is compatible with the long-term clinical aspect of the disease and provides a basis for stem cell protective therapies in the treatment of aGVHD.
Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty University Hospital Aachen, Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany;
Sebastian
S
Hummel
Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty University Hospital Aachen, Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany;
Mónica S
MS
Ventura Ferreira
Department of Hematology and Oncology, Internal Medicine III, and.
Daniel
D
Heudobler
Institute of Pathology, University Hospital of Regensburg, Regensburg, Germany;
Elisabeth
E
Huber
Department of Biochemistry and Molecular Biology, Interdisciplinary Center for Clinical Research Immunohistochemistry and Confocal Microscopy Unit, and.
Dirk
D
Fahrenkamp
Institute for Experimental Molecular Imaging, University Hospital Aachen, Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany; and.
Felix
F
Gremse
Department of Hematology and Oncology, Internal Medicine III, and.
Karin
K
Schmid
Department of Biochemistry and Molecular Biology, Interdisciplinary Center for Clinical Research Immunohistochemistry and Confocal Microscopy Unit, and.
Gerhard
G
Müller-Newen
Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty University Hospital Aachen, Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany;
Patrick
P
Ziegler
Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty University Hospital Aachen, Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany;
Edgar
E
Jost
Telomere and Telomerase Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
Maria A
MA
Blasco
Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty University Hospital Aachen, Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany;
Tim H
TH
Brümmendorf
Department of Hematology and Oncology, Internal Medicine III, and.
Ernst
E
Holler
Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty University Hospital Aachen, Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany;
Fabian
F
Beier
D000208:Acute Disease; D064591:Allografts; D049109:Cell Proliferation; D020895:Enterocytes / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006086:Graft vs Host Disease / Q000378:metabolism* / Q000473:pathology; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007410:Intestinal Diseases / Q000378:metabolism* / Q000473:pathology; D008297:Male; D012189:Retrospective Studies; D059506:Telomere Shortening