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Nat Med. 2014 Jun;20(6):648-54. doi: 10.1038/nm.3517. Epub 2014 May 18.

Neutrophil granulocytes recruited upon translocation of intestinal bacteria enhance graft-versus-host disease via tissue damage.

Author information

1
1] Department of Hematology and Oncology, University Medical Center, Freiburg, Germany. [2].
2
1] Department of Hematology and Oncology, University Medical Center, Freiburg, Germany. [2] Faculty of Biology, Albert-Ludwigs-University, Freiburg, Germany. [3].
3
1] Division of Hematology and Oncology, Louisiana State University Health Sciences Center Shreveport, Shreveport, Louisiana, USA. [2] Division of Bone Marrow Transplantation, University of Utah School of Medicine, Huntsman Cancer Institute, Salt Lake City, Utah, USA. [3].
4
1] Faculty of Biology, Albert-Ludwigs-University, Freiburg, Germany. [2] Department of Medical Microbiology and Hygiene, University Medical Center, Freiburg, Germany. [3] Spemann Graduate School of Biology and Medicine, Albert-Ludwigs-University Freiburg, Germany.
5
Center of Chronic Immunodeficiency, Albert-Ludwigs-University Freiburg, Germany.
6
Department of Physiology, Semmelweis University School of Medicine, Budapest, Hungary.
7
Department of Radiology Medical Physics, University Medical Center, Freiburg, Germany.
8
Division of Hematology and Oncology, Louisiana State University Health Sciences Center Shreveport, Shreveport, Louisiana, USA.
9
1] Division of Hematology and Oncology, Louisiana State University Health Sciences Center Shreveport, Shreveport, Louisiana, USA. [2] Division of Bone Marrow Transplantation, University of Utah School of Medicine, Huntsman Cancer Institute, Salt Lake City, Utah, USA.
10
1] Department of Hematology and Oncology, University Medical Center, Freiburg, Germany. [2] Faculty of Biology, Albert-Ludwigs-University, Freiburg, Germany.
11
Department of Pathology, University Medical Center, Albert-Ludwigs-University, Freiburg, Germany.
12
1] Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany. [2] Centre for Biological Signaling Studies BIOSS, Albert-Ludwigs-University Freiburg, Germany.
13
Department of Medical Microbiology and Hygiene, University Medical Center, Freiburg, Germany.
14
Department of Urology, University Medical Center, Freiburg, Germany.
15
Department of Hematology and Oncology, University Medical Center, Freiburg, Germany.
16
Allergy Research Group, Department of Dermatology, University Medical Center, University Freiburg, Germany.
17
1] Spemann Graduate School of Biology and Medicine, Albert-Ludwigs-University Freiburg, Germany. [2] Department of Neuropathology, University Medical Center, Freiburg, Germany.
18
1] Center of Chronic Immunodeficiency, Albert-Ludwigs-University Freiburg, Germany. [2] Center for Pediatrics and Adolescent Medicine, University Medical Center, Freiburg, Germany.
19
Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
20
1] Department of Medical Microbiology and Hygiene, University Medical Center, Freiburg, Germany. [2] Spemann Graduate School of Biology and Medicine, Albert-Ludwigs-University Freiburg, Germany. [3].
21
1] Department of Hematology and Oncology, University Medical Center, Freiburg, Germany. [2] Spemann Graduate School of Biology and Medicine, Albert-Ludwigs-University Freiburg, Germany. [3] Centre for Biological Signaling Studies BIOSS, Albert-Ludwigs-University Freiburg, Germany. [4].

Abstract

Acute graft-versus-host disease (GVHD) considerably limits wider usage of allogeneic hematopoietic cell transplantation (allo-HCT). Antigen-presenting cells and T cells are populations customarily associated with GVHD pathogenesis. Of note, neutrophils are the largest human white blood cell population. The cells cleave chemokines and produce reactive oxygen species, thereby promoting T cell activation. Therefore, during an allogeneic immune response, neutrophils could amplify tissue damage caused by conditioning regimens. We analyzed neutrophil infiltration of the mouse ileum after allo-HCT by in vivo myeloperoxidase imaging and found that infiltration levels were dependent on the local microbial flora and were not detectable under germ-free conditions. Physical or genetic depletion of neutrophils reduced GVHD-related mortality. The contribution of neutrophils to GVHD severity required reactive oxygen species (ROS) because selective Cybb (encoding cytochrome b-245, beta polypeptide, also known as NOX2) deficiency in neutrophils impairing ROS production led to lower levels of tissue damage, GVHD-related mortality and effector phenotype T cells. Enhanced survival of Bcl-xL transgenic neutrophils increased GVHD severity. In contrast, when we transferred neutrophils lacking Toll-like receptor-2 (TLR2), TLR3, TLR4, TLR7 and TLR9, which are normally less strongly activated by translocating bacteria, into wild-type C57BL/6 mice, GVHD severity was reduced. In humans, severity of intestinal GVHD strongly correlated with levels of neutrophils present in GVHD lesions. This study describes a new potential role for neutrophils in the pathogenesis of GVHD in both mice and humans.

Comment in

PMID:
24836575
DOI:
10.1038/nm.3517
[Indexed for MEDLINE]
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