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Research ArticleHematologyTransplantation
Open Access | 
10.1172/jci.insight.154250
1Interdisciplinary Center for Clinical Research (IZKF), Experimental Stem Cell Transplantation Laboratory, and
2Department of Internal Medicine II, Würzburg University Hospital, Würzburg, Germany.
3Graduate School of Life Sciences, Würzburg University, Würzburg, Germany.
4Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
5Department of Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
6Institute for Virology and Immunobiology, Würzburg University, Würzburg, Germany.
7Mildred Scheel Early Career Centre, University Hospital of Würzburg, Würzburg, Germany.
8Department of Nephropathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
9Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany.
10Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz-Center for Infection (HZI), Würzburg, Germany.
11Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland.
12Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
13Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany.
Address correspondence to: Andreas Beilhack, IZKF Forschergruppe für Experimentelle Stammzelltransplantation, Medizinische Klinik und Poliklinik II, ZEMM - Zinklesweg 10, D-97080 Würzburg, Germany. Phone: 49.931.201.44040; Email: beilhack_a@ukw.de.
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Shaikh, H.
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1Interdisciplinary Center for Clinical Research (IZKF), Experimental Stem Cell Transplantation Laboratory, and
2Department of Internal Medicine II, Würzburg University Hospital, Würzburg, Germany.
3Graduate School of Life Sciences, Würzburg University, Würzburg, Germany.
4Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
5Department of Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
6Institute for Virology and Immunobiology, Würzburg University, Würzburg, Germany.
7Mildred Scheel Early Career Centre, University Hospital of Würzburg, Würzburg, Germany.
8Department of Nephropathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
9Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany.
10Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz-Center for Infection (HZI), Würzburg, Germany.
11Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland.
12Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
13Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany.
Address correspondence to: Andreas Beilhack, IZKF Forschergruppe für Experimentelle Stammzelltransplantation, Medizinische Klinik und Poliklinik II, ZEMM - Zinklesweg 10, D-97080 Würzburg, Germany. Phone: 49.931.201.44040; Email: beilhack_a@ukw.de.
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1Interdisciplinary Center for Clinical Research (IZKF), Experimental Stem Cell Transplantation Laboratory, and
2Department of Internal Medicine II, Würzburg University Hospital, Würzburg, Germany.
3Graduate School of Life Sciences, Würzburg University, Würzburg, Germany.
4Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
5Department of Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
6Institute for Virology and Immunobiology, Würzburg University, Würzburg, Germany.
7Mildred Scheel Early Career Centre, University Hospital of Würzburg, Würzburg, Germany.
8Department of Nephropathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
9Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany.
10Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz-Center for Infection (HZI), Würzburg, Germany.
11Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland.
12Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
13Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany.
Address correspondence to: Andreas Beilhack, IZKF Forschergruppe für Experimentelle Stammzelltransplantation, Medizinische Klinik und Poliklinik II, ZEMM - Zinklesweg 10, D-97080 Würzburg, Germany. Phone: 49.931.201.44040; Email: beilhack_a@ukw.de.
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Mokhtari, Z.
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1Interdisciplinary Center for Clinical Research (IZKF), Experimental Stem Cell Transplantation Laboratory, and
2Department of Internal Medicine II, Würzburg University Hospital, Würzburg, Germany.
3Graduate School of Life Sciences, Würzburg University, Würzburg, Germany.
4Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
5Department of Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
6Institute for Virology and Immunobiology, Würzburg University, Würzburg, Germany.
7Mildred Scheel Early Career Centre, University Hospital of Würzburg, Würzburg, Germany.
8Department of Nephropathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
9Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany.
10Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz-Center for Infection (HZI), Würzburg, Germany.
11Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland.
12Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
13Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany.
Address correspondence to: Andreas Beilhack, IZKF Forschergruppe für Experimentelle Stammzelltransplantation, Medizinische Klinik und Poliklinik II, ZEMM - Zinklesweg 10, D-97080 Würzburg, Germany. Phone: 49.931.201.44040; Email: beilhack_a@ukw.de.
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1Interdisciplinary Center for Clinical Research (IZKF), Experimental Stem Cell Transplantation Laboratory, and
2Department of Internal Medicine II, Würzburg University Hospital, Würzburg, Germany.
3Graduate School of Life Sciences, Würzburg University, Würzburg, Germany.
4Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
5Department of Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
6Institute for Virology and Immunobiology, Würzburg University, Würzburg, Germany.
7Mildred Scheel Early Career Centre, University Hospital of Würzburg, Würzburg, Germany.
8Department of Nephropathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
9Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany.
10Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz-Center for Infection (HZI), Würzburg, Germany.
11Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland.
12Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
13Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany.
Address correspondence to: Andreas Beilhack, IZKF Forschergruppe für Experimentelle Stammzelltransplantation, Medizinische Klinik und Poliklinik II, ZEMM - Zinklesweg 10, D-97080 Würzburg, Germany. Phone: 49.931.201.44040; Email: beilhack_a@ukw.de.
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1Interdisciplinary Center for Clinical Research (IZKF), Experimental Stem Cell Transplantation Laboratory, and
2Department of Internal Medicine II, Würzburg University Hospital, Würzburg, Germany.
3Graduate School of Life Sciences, Würzburg University, Würzburg, Germany.
4Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
5Department of Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
6Institute for Virology and Immunobiology, Würzburg University, Würzburg, Germany.
7Mildred Scheel Early Career Centre, University Hospital of Würzburg, Würzburg, Germany.
8Department of Nephropathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
9Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany.
10Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz-Center for Infection (HZI), Würzburg, Germany.
11Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland.
12Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
13Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany.
Address correspondence to: Andreas Beilhack, IZKF Forschergruppe für Experimentelle Stammzelltransplantation, Medizinische Klinik und Poliklinik II, ZEMM - Zinklesweg 10, D-97080 Würzburg, Germany. Phone: 49.931.201.44040; Email: beilhack_a@ukw.de.
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1Interdisciplinary Center for Clinical Research (IZKF), Experimental Stem Cell Transplantation Laboratory, and
2Department of Internal Medicine II, Würzburg University Hospital, Würzburg, Germany.
3Graduate School of Life Sciences, Würzburg University, Würzburg, Germany.
4Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
5Department of Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
6Institute for Virology and Immunobiology, Würzburg University, Würzburg, Germany.
7Mildred Scheel Early Career Centre, University Hospital of Würzburg, Würzburg, Germany.
8Department of Nephropathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
9Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany.
10Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz-Center for Infection (HZI), Würzburg, Germany.
11Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland.
12Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
13Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany.
Address correspondence to: Andreas Beilhack, IZKF Forschergruppe für Experimentelle Stammzelltransplantation, Medizinische Klinik und Poliklinik II, ZEMM - Zinklesweg 10, D-97080 Würzburg, Germany. Phone: 49.931.201.44040; Email: beilhack_a@ukw.de.
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1Interdisciplinary Center for Clinical Research (IZKF), Experimental Stem Cell Transplantation Laboratory, and
2Department of Internal Medicine II, Würzburg University Hospital, Würzburg, Germany.
3Graduate School of Life Sciences, Würzburg University, Würzburg, Germany.
4Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
5Department of Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
6Institute for Virology and Immunobiology, Würzburg University, Würzburg, Germany.
7Mildred Scheel Early Career Centre, University Hospital of Würzburg, Würzburg, Germany.
8Department of Nephropathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
9Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany.
10Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz-Center for Infection (HZI), Würzburg, Germany.
11Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland.
12Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
13Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany.
Address correspondence to: Andreas Beilhack, IZKF Forschergruppe für Experimentelle Stammzelltransplantation, Medizinische Klinik und Poliklinik II, ZEMM - Zinklesweg 10, D-97080 Würzburg, Germany. Phone: 49.931.201.44040; Email: beilhack_a@ukw.de.
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1Interdisciplinary Center for Clinical Research (IZKF), Experimental Stem Cell Transplantation Laboratory, and
2Department of Internal Medicine II, Würzburg University Hospital, Würzburg, Germany.
3Graduate School of Life Sciences, Würzburg University, Würzburg, Germany.
4Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
5Department of Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
6Institute for Virology and Immunobiology, Würzburg University, Würzburg, Germany.
7Mildred Scheel Early Career Centre, University Hospital of Würzburg, Würzburg, Germany.
8Department of Nephropathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
9Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany.
10Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz-Center for Infection (HZI), Würzburg, Germany.
11Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland.
12Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
13Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany.
Address correspondence to: Andreas Beilhack, IZKF Forschergruppe für Experimentelle Stammzelltransplantation, Medizinische Klinik und Poliklinik II, ZEMM - Zinklesweg 10, D-97080 Würzburg, Germany. Phone: 49.931.201.44040; Email: beilhack_a@ukw.de.
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1Interdisciplinary Center for Clinical Research (IZKF), Experimental Stem Cell Transplantation Laboratory, and
2Department of Internal Medicine II, Würzburg University Hospital, Würzburg, Germany.
3Graduate School of Life Sciences, Würzburg University, Würzburg, Germany.
4Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
5Department of Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
6Institute for Virology and Immunobiology, Würzburg University, Würzburg, Germany.
7Mildred Scheel Early Career Centre, University Hospital of Würzburg, Würzburg, Germany.
8Department of Nephropathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
9Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany.
10Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz-Center for Infection (HZI), Würzburg, Germany.
11Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland.
12Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
13Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany.
Address correspondence to: Andreas Beilhack, IZKF Forschergruppe für Experimentelle Stammzelltransplantation, Medizinische Klinik und Poliklinik II, ZEMM - Zinklesweg 10, D-97080 Würzburg, Germany. Phone: 49.931.201.44040; Email: beilhack_a@ukw.de.
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1Interdisciplinary Center for Clinical Research (IZKF), Experimental Stem Cell Transplantation Laboratory, and
2Department of Internal Medicine II, Würzburg University Hospital, Würzburg, Germany.
3Graduate School of Life Sciences, Würzburg University, Würzburg, Germany.
4Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
5Department of Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
6Institute for Virology and Immunobiology, Würzburg University, Würzburg, Germany.
7Mildred Scheel Early Career Centre, University Hospital of Würzburg, Würzburg, Germany.
8Department of Nephropathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
9Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany.
10Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz-Center for Infection (HZI), Würzburg, Germany.
11Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland.
12Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
13Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany.
Address correspondence to: Andreas Beilhack, IZKF Forschergruppe für Experimentelle Stammzelltransplantation, Medizinische Klinik und Poliklinik II, ZEMM - Zinklesweg 10, D-97080 Würzburg, Germany. Phone: 49.931.201.44040; Email: beilhack_a@ukw.de.
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Lutz, M.
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1Interdisciplinary Center for Clinical Research (IZKF), Experimental Stem Cell Transplantation Laboratory, and
2Department of Internal Medicine II, Würzburg University Hospital, Würzburg, Germany.
3Graduate School of Life Sciences, Würzburg University, Würzburg, Germany.
4Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
5Department of Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
6Institute for Virology and Immunobiology, Würzburg University, Würzburg, Germany.
7Mildred Scheel Early Career Centre, University Hospital of Würzburg, Würzburg, Germany.
8Department of Nephropathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
9Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany.
10Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz-Center for Infection (HZI), Würzburg, Germany.
11Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland.
12Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
13Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany.
Address correspondence to: Andreas Beilhack, IZKF Forschergruppe für Experimentelle Stammzelltransplantation, Medizinische Klinik und Poliklinik II, ZEMM - Zinklesweg 10, D-97080 Würzburg, Germany. Phone: 49.931.201.44040; Email: beilhack_a@ukw.de.
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1Interdisciplinary Center for Clinical Research (IZKF), Experimental Stem Cell Transplantation Laboratory, and
2Department of Internal Medicine II, Würzburg University Hospital, Würzburg, Germany.
3Graduate School of Life Sciences, Würzburg University, Würzburg, Germany.
4Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
5Department of Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
6Institute for Virology and Immunobiology, Würzburg University, Würzburg, Germany.
7Mildred Scheel Early Career Centre, University Hospital of Würzburg, Würzburg, Germany.
8Department of Nephropathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
9Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany.
10Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz-Center for Infection (HZI), Würzburg, Germany.
11Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland.
12Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
13Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany.
Address correspondence to: Andreas Beilhack, IZKF Forschergruppe für Experimentelle Stammzelltransplantation, Medizinische Klinik und Poliklinik II, ZEMM - Zinklesweg 10, D-97080 Würzburg, Germany. Phone: 49.931.201.44040; Email: beilhack_a@ukw.de.
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1Interdisciplinary Center for Clinical Research (IZKF), Experimental Stem Cell Transplantation Laboratory, and
2Department of Internal Medicine II, Würzburg University Hospital, Würzburg, Germany.
3Graduate School of Life Sciences, Würzburg University, Würzburg, Germany.
4Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
5Department of Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
6Institute for Virology and Immunobiology, Würzburg University, Würzburg, Germany.
7Mildred Scheel Early Career Centre, University Hospital of Würzburg, Würzburg, Germany.
8Department of Nephropathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
9Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany.
10Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz-Center for Infection (HZI), Würzburg, Germany.
11Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland.
12Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
13Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany.
Address correspondence to: Andreas Beilhack, IZKF Forschergruppe für Experimentelle Stammzelltransplantation, Medizinische Klinik und Poliklinik II, ZEMM - Zinklesweg 10, D-97080 Würzburg, Germany. Phone: 49.931.201.44040; Email: beilhack_a@ukw.de.
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Zernecke, A.
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1Interdisciplinary Center for Clinical Research (IZKF), Experimental Stem Cell Transplantation Laboratory, and
2Department of Internal Medicine II, Würzburg University Hospital, Würzburg, Germany.
3Graduate School of Life Sciences, Würzburg University, Würzburg, Germany.
4Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
5Department of Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
6Institute for Virology and Immunobiology, Würzburg University, Würzburg, Germany.
7Mildred Scheel Early Career Centre, University Hospital of Würzburg, Würzburg, Germany.
8Department of Nephropathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
9Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany.
10Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz-Center for Infection (HZI), Würzburg, Germany.
11Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland.
12Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
13Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany.
Address correspondence to: Andreas Beilhack, IZKF Forschergruppe für Experimentelle Stammzelltransplantation, Medizinische Klinik und Poliklinik II, ZEMM - Zinklesweg 10, D-97080 Würzburg, Germany. Phone: 49.931.201.44040; Email: beilhack_a@ukw.de.
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Einsele, H.
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1Interdisciplinary Center for Clinical Research (IZKF), Experimental Stem Cell Transplantation Laboratory, and
2Department of Internal Medicine II, Würzburg University Hospital, Würzburg, Germany.
3Graduate School of Life Sciences, Würzburg University, Würzburg, Germany.
4Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
5Department of Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
6Institute for Virology and Immunobiology, Würzburg University, Würzburg, Germany.
7Mildred Scheel Early Career Centre, University Hospital of Würzburg, Würzburg, Germany.
8Department of Nephropathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
9Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany.
10Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz-Center for Infection (HZI), Würzburg, Germany.
11Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland.
12Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
13Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany.
Address correspondence to: Andreas Beilhack, IZKF Forschergruppe für Experimentelle Stammzelltransplantation, Medizinische Klinik und Poliklinik II, ZEMM - Zinklesweg 10, D-97080 Würzburg, Germany. Phone: 49.931.201.44040; Email: beilhack_a@ukw.de.
Find articles by Saliba, A. in: JCI | PubMed | Google Scholar
1Interdisciplinary Center for Clinical Research (IZKF), Experimental Stem Cell Transplantation Laboratory, and
2Department of Internal Medicine II, Würzburg University Hospital, Würzburg, Germany.
3Graduate School of Life Sciences, Würzburg University, Würzburg, Germany.
4Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
5Department of Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
6Institute for Virology and Immunobiology, Würzburg University, Würzburg, Germany.
7Mildred Scheel Early Career Centre, University Hospital of Würzburg, Würzburg, Germany.
8Department of Nephropathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
9Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany.
10Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz-Center for Infection (HZI), Würzburg, Germany.
11Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland.
12Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
13Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany.
Address correspondence to: Andreas Beilhack, IZKF Forschergruppe für Experimentelle Stammzelltransplantation, Medizinische Klinik und Poliklinik II, ZEMM - Zinklesweg 10, D-97080 Würzburg, Germany. Phone: 49.931.201.44040; Email: beilhack_a@ukw.de.
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1Interdisciplinary Center for Clinical Research (IZKF), Experimental Stem Cell Transplantation Laboratory, and
2Department of Internal Medicine II, Würzburg University Hospital, Würzburg, Germany.
3Graduate School of Life Sciences, Würzburg University, Würzburg, Germany.
4Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
5Department of Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
6Institute for Virology and Immunobiology, Würzburg University, Würzburg, Germany.
7Mildred Scheel Early Career Centre, University Hospital of Würzburg, Würzburg, Germany.
8Department of Nephropathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
9Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany.
10Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz-Center for Infection (HZI), Würzburg, Germany.
11Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland.
12Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
13Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany.
Address correspondence to: Andreas Beilhack, IZKF Forschergruppe für Experimentelle Stammzelltransplantation, Medizinische Klinik und Poliklinik II, ZEMM - Zinklesweg 10, D-97080 Würzburg, Germany. Phone: 49.931.201.44040; Email: beilhack_a@ukw.de.
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Huehn, J.
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1Interdisciplinary Center for Clinical Research (IZKF), Experimental Stem Cell Transplantation Laboratory, and
2Department of Internal Medicine II, Würzburg University Hospital, Würzburg, Germany.
3Graduate School of Life Sciences, Würzburg University, Würzburg, Germany.
4Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
5Department of Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
6Institute for Virology and Immunobiology, Würzburg University, Würzburg, Germany.
7Mildred Scheel Early Career Centre, University Hospital of Würzburg, Würzburg, Germany.
8Department of Nephropathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
9Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany.
10Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz-Center for Infection (HZI), Würzburg, Germany.
11Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland.
12Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
13Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany.
Address correspondence to: Andreas Beilhack, IZKF Forschergruppe für Experimentelle Stammzelltransplantation, Medizinische Klinik und Poliklinik II, ZEMM - Zinklesweg 10, D-97080 Würzburg, Germany. Phone: 49.931.201.44040; Email: beilhack_a@ukw.de.
Find articles by
Beilhack, A.
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Published October 13, 2022 - More info
Published in Volume 7, Issue 22 on November 22, 2022
AbstractAcute graft versus host disease (aGvHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT) inflicted by alloreactive T cells primed in secondary lymphoid organs (SLOs) and subsequent damage to aGvHD target tissues. In recent years, Treg transfer and/or expansion has emerged as a promising therapy to modulate aGvHD. However, cellular niches essential for fostering Tregs to prevent aGvHD have not been explored. Here, we tested whether and to what extent MHC class II (MHCII) expressed on Ccl19+ fibroblastic reticular cells (FRCs) shape the donor CD4+ T cell response during aGvHD. Animals lacking MHCII expression on Ccl19-Cre–expressing FRCs (MHCIIΔCcl19) showed aberrant CD4+ T cell activation in the effector phase, resulting in exacerbated aGvHD that was associated with significantly reduced expansion of Foxp3+ Tregs and invariant NK T (iNKT) cells. Skewed Treg maintenance in MHCIIΔCcl19 mice resulted in loss of protection from aGvHD provided by adoptively transferred donor Tregs. In contrast, although FRCs upregulated costimulatory surface receptors, and although they degraded and processed exogenous antigens after myeloablative irradiation, FRCs were dispensable to activate alloreactive CD4+ T cells in 2 mouse models of aGvHD. In summary, these data reveal an immunoprotective, MHCII-mediated function of FRC niches in secondary lymphoid organs (SLOs) after allo-HCT and highlight a framework of cellular and molecular interactions that regulate CD4+ T cell alloimmunity.
Graphical Abstract
Introduction
Hematopoietic cell transplantation (HCT) is the only reliable curative therapy for various hematological malignancies and genetic hematological disorders (1–3). Nevertheless, acute graft versus host disease (aGvHD) remains the leading cause of morbidity and mortality (20%) of transplant-related complications following allogeneic HCT (allo-HCT) (4, 5). FoxP3-expressing Tregs are pivotal for the regulation of self-reactive T cells and autoimmunity (6) and have been clinically shown to prevent aGvHD without impairing the graft versus leukemia (GvL) effect (7, 8). However, the cellular niches that are essentially required to foster Treg homeostasis and function after allo-HCT have not been fully addressed.
Secondary lymphoid organs (SLOs) serve as initiation sites of aGvHD (9). Within SLOs, nonhematopoietic lymph node stromal cells (LNSCs) provide the infrastructure to maintain immune homeostasis and facilitate rapid and effective immune responses (10–12). Fibroblastic reticular cells (FRCs) are immunologically specialized fibroblasts of mesenchymal origin and comprise 20%–50% of the nonhematopoietic compartment of SLOs (13, 14) forming the conduit network, maintaining the reticular network tension and LN expansion (15). Furthermore, FRCs are a major source of naive T/B cell survival factors (16, 17) and secrete the homeostatic chemokines CCL19 and CCL21 to mediate the recruitment of CCR7-expressing naive T cells (18). Activated FRCs play a crucial role in both limiting (19–23) and promoting (24, 25) T cell responses. FRCs reportedly express MHC class II (MHCII) and directly acquire self-peptide/MHCII complexes from DCs to present to and tolerize antigen-specific CD4+ T cells (26, 27). Furthermore, FRCs indirectly restrain aberrant CD4+ T cell activation via MHCII presentation of self-antigen to induce proliferation of Tregs (
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