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

Lukas Schwab, Luise Goroncy, Senthilnathan Palaniyandi, Sanjivan Gautam, Antigoni Triantafyllopoulou, A. Mócsai, Wilfried Reichardt, Fridrik J. Karlsson, Sabarinath V. Radhakrishnan, Kathrin Hanke, Annette Schmitt-Graeff, Marina Freudenberg, Friederike D. Von Loewenich, Philipp Wolf, Franziska Leonhardt, Nicoleta Baxan, Dietmar Pfeifer, Oliver Schmah, Anne Schönle, Stefan F. Martin & 9 others Roland Mertelsmann, Justus Duyster, Jürgen Finke, Marco Prinz, Philipp Henneke, Hans Häcker, Gerhard C. Hildebrandt, Georg Häcker, Robert Zeiser

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)648-654
Number of pages7
JournalNature Medicine
Volume20
Issue number6
DOIs
Publication statusPublished - 2014

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Graft vs Host Disease
Granulocytes
Grafts
Bacteria
Neutrophils
Tissue
T-cells
Reactive Oxygen Species
Cell Transplantation
T-Lymphocytes
Infiltration
Toll-Like Receptor 2
Neutrophil Infiltration
Mortality
Antigen-Presenting Cells
Inbred C57BL Mouse
Ileum
Chemokines
Population
Peroxidase

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Neutrophil granulocytes recruited upon translocation of intestinal bacteria enhance graft-versus-host disease via tissue damage. / Schwab, Lukas; Goroncy, Luise; Palaniyandi, Senthilnathan; Gautam, Sanjivan; Triantafyllopoulou, Antigoni; Mócsai, A.; Reichardt, Wilfried; Karlsson, Fridrik J.; Radhakrishnan, Sabarinath V.; Hanke, Kathrin; Schmitt-Graeff, Annette; Freudenberg, Marina; Von Loewenich, Friederike D.; Wolf, Philipp; Leonhardt, Franziska; Baxan, Nicoleta; Pfeifer, Dietmar; Schmah, Oliver; Schönle, Anne; Martin, Stefan F.; Mertelsmann, Roland; Duyster, Justus; Finke, Jürgen; Prinz, Marco; Henneke, Philipp; Häcker, Hans; Hildebrandt, Gerhard C.; Häcker, Georg; Zeiser, Robert.

In: Nature Medicine, Vol. 20, No. 6, 2014, p. 648-654.

Research output: Contribution to journalArticle

Schwab, L, Goroncy, L, Palaniyandi, S, Gautam, S, Triantafyllopoulou, A, Mócsai, A, Reichardt, W, Karlsson, FJ, Radhakrishnan, SV, Hanke, K, Schmitt-Graeff, A, Freudenberg, M, Von Loewenich, FD, Wolf, P, Leonhardt, F, Baxan, N, Pfeifer, D, Schmah, O, Schönle, A, Martin, SF, Mertelsmann, R, Duyster, J, Finke, J, Prinz, M, Henneke, P, Häcker, H, Hildebrandt, GC, Häcker, G & Zeiser, R 2014, 'Neutrophil granulocytes recruited upon translocation of intestinal bacteria enhance graft-versus-host disease via tissue damage', Nature Medicine, vol. 20, no. 6, pp. 648-654. https://doi.org/10.1038/nm.3517
Schwab, Lukas ; Goroncy, Luise ; Palaniyandi, Senthilnathan ; Gautam, Sanjivan ; Triantafyllopoulou, Antigoni ; Mócsai, A. ; Reichardt, Wilfried ; Karlsson, Fridrik J. ; Radhakrishnan, Sabarinath V. ; Hanke, Kathrin ; Schmitt-Graeff, Annette ; Freudenberg, Marina ; Von Loewenich, Friederike D. ; Wolf, Philipp ; Leonhardt, Franziska ; Baxan, Nicoleta ; Pfeifer, Dietmar ; Schmah, Oliver ; Schönle, Anne ; Martin, Stefan F. ; Mertelsmann, Roland ; Duyster, Justus ; Finke, Jürgen ; Prinz, Marco ; Henneke, Philipp ; Häcker, Hans ; Hildebrandt, Gerhard C. ; Häcker, Georg ; Zeiser, Robert. / Neutrophil granulocytes recruited upon translocation of intestinal bacteria enhance graft-versus-host disease via tissue damage. In: Nature Medicine. 2014 ; Vol. 20, No. 6. pp. 648-654.
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