title: Exogenous TNFR2 activation protects from acute GvHD via host T reg cell expansion.
abstract: Donor CD4(+)Foxp3(+) regulatory T cells (T reg cells) suppress graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (HCT [allo-HCT]). Current clinical study protocols rely on the ex vivo expansion of donor T reg cells and their infusion in high numbers. In this study, we present a novel strategy for inhibiting GvHD that is based on the in vivo expansion of recipient T reg cells before allo-HCT, exploiting the crucial role of tumor necrosis factor receptor 2 (TNFR2) in T reg cell biology. Expanding radiation-resistant host T reg cells in recipient mice using a mouse TNFR2-selective agonist before allo-HCT significantly prolonged survival and reduced GvHD severity in a TNFR2- and T reg cell-dependent manner. The beneficial effects of transplanted T cells against leukemia cells and infectious pathogens remained unaffected. A corresponding human TNFR2-specific agonist expanded human T reg cells in vitro. These observations indicate the potential of our strategy to protect allo-HCT patients from acute GvHD by expanding T reg cells via selective TNFR2 activation in vivo.
authors.affiliation: Department of Internal Medicine II, University Hospital Würzburg, Würzburg University, 97080 Würzburg, Germany Center for Interdisciplinary Clinical Research, Würzburg University, 97080 Würzburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Chopra
authors.affiliation: Department of Internal Medicine II, University Hospital Würzburg, Würzburg University, 97080 Würzburg, Germany Center for Interdisciplinary Clinical Research, Würzburg University, 97080 Würzburg, Germany.
authors.forename: Marlene
authors.identifier: 0000-0003-4562-9147
authors.initials: M
authors.lastname: Biehl
authors.affiliation: Department of Internal Medicine II, University Hospital Würzburg, Würzburg University, 97080 Würzburg, Germany Center for Interdisciplinary Clinical Research, Würzburg University, 97080 Würzburg, Germany Graduate School of Life Sciences, Würzburg University, 97080 Würzburg, Germany.
authors.forename: Tim
authors.identifier: 0000-0002-2803-5374
authors.initials: T
authors.lastname: Steinfatt
authors.affiliation: Department of Internal Medicine II, University Hospital Würzburg, Würzburg University, 97080 Würzburg, Germany Center for Interdisciplinary Clinical Research, Würzburg University, 97080 Würzburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Brandl
authors.affiliation: Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, Würzburg University, 97080 Würzburg, Germany.
authors.forename: Juliane
authors.identifier: 0000-0002-7097-1916
authors.initials: J
authors.lastname: Kums
authors.affiliation: Department of Internal Medicine II, University Hospital Würzburg, Würzburg University, 97080 Würzburg, Germany Center for Interdisciplinary Clinical Research, Würzburg University, 97080 Würzburg, Germany.
authors.forename: Jorge
authors.initials: J
authors.lastname: Amich
authors.affiliation: Department of Molecular Pathology, Institute of Pathology, Würzburg University, 97080 Würzburg, Germany.
authors.forename: Martin
authors.identifier: 0000-0001-8974-7052
authors.initials: M
authors.lastname: Vaeth
authors.affiliation: Department of Molecular Pathology, Institute of Pathology, Würzburg University, 97080 Würzburg, Germany.
authors.forename: Janina
authors.identifier: 0000-0001-5435-6852
authors.initials: J
authors.lastname: Kuen
authors.affiliation: Institute for Virology and Research Center of Immunotherapy, University Medical Center of the Johannes Gutenberg-University, 55131 Mainz, Germany.
authors.forename: Rafaela
authors.identifier: 0000-0001-5767-5111
authors.initials: R
authors.lastname: Holtappels
authors.affiliation: Institute for Virology and Research Center of Immunotherapy, University Medical Center of the Johannes Gutenberg-University, 55131 Mainz, Germany.
authors.forename: Jürgen
authors.identifier: 0000-0002-7062-9088
authors.initials: J
authors.lastname: Podlech
authors.affiliation: Institute of Pathology, Würzburg University, 97080 Würzburg, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Mottok
authors.affiliation: Department of Internal Medicine II, University Hospital Würzburg, Würzburg University, 97080 Würzburg, Germany Center for Interdisciplinary Clinical Research, Würzburg University, 97080 Würzburg, Germany.
authors.forename: Sabrina
authors.identifier: 0000-0001-8954-4220
authors.initials: S
authors.lastname: Kraus
authors.affiliation: Department of Internal Medicine II, University Hospital Würzburg, Würzburg University, 97080 Würzburg, Germany Center for Interdisciplinary Clinical Research, Würzburg University, 97080 Würzburg, Germany Graduate School of Life Sciences, Würzburg University, 97080 Würzburg, Germany.
authors.forename: Ana-Laura
authors.initials: AL
authors.lastname: Jordán-Garrote
authors.affiliation: Department of Internal Medicine II, University Hospital Würzburg, Würzburg University, 97080 Würzburg, Germany Center for Interdisciplinary Clinical Research, Würzburg University, 97080 Würzburg, Germany Graduate School of Life Sciences, Würzburg University, 97080 Würzburg, Germany.
authors.forename: Carina A
authors.initials: CA
authors.lastname: Bäuerlein
authors.affiliation: Department of Internal Medicine II, University Hospital Würzburg, Würzburg University, 97080 Würzburg, Germany Center for Interdisciplinary Clinical Research, Würzburg University, 97080 Würzburg, Germany Graduate School of Life Sciences, Würzburg University, 97080 Würzburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Brede
authors.affiliation: Institute for Virology and Immunobiology, Würzburg University, 97080 Würzburg, Germany.
authors.forename: Eliana
authors.initials: E
authors.lastname: Ribechini
authors.affiliation: Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, Würzburg University, 97080 Würzburg, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Fick
authors.affiliation: Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, Würzburg University, 97080 Würzburg, Germany.
authors.forename: Axel
authors.identifier: 0000-0003-2169-9351
authors.initials: A
authors.lastname: Seher
authors.affiliation: Institute of Immunology, Regensburg University, 93053 Regensburg, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Polz
authors.affiliation: Department of Internal Medicine II, University Hospital Würzburg, Würzburg University, 97080 Würzburg, Germany Center for Interdisciplinary Clinical Research, Würzburg University, 97080 Würzburg, Germany Graduate School of Life Sciences, Würzburg University, 97080 Würzburg, Germany.
authors.forename: Katja J
authors.identifier: 0000-0001-5162-7266
authors.initials: KJ
authors.lastname: Ottmüller
authors.affiliation: Blood and Marrow Transplantation, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Jeanette
authors.identifier: 0000-0002-0753-0317
authors.initials: J
authors.lastname: Baker
authors.affiliation: Blood and Marrow Transplantation, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Nishikii
authors.affiliation: Department of Internal Medicine II, University Hospital Würzburg, Würzburg University, 97080 Würzburg, Germany Center for Interdisciplinary Clinical Research, Würzburg University, 97080 Würzburg, Germany.
authors.forename: Miriam
authors.identifier: 0000-0002-7872-8697
authors.initials: M
authors.lastname: Ritz
authors.affiliation: Department of Internal Medicine II, University Hospital Würzburg, Würzburg University, 97080 Würzburg, Germany Center for Interdisciplinary Clinical Research, Würzburg University, 97080 Würzburg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Mattenheimer
authors.affiliation: Department of Internal Medicine II, University Hospital Würzburg, Würzburg University, 97080 Würzburg, Germany Center for Interdisciplinary Clinical Research, Würzburg University, 97080 Würzburg, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Schwinn
authors.affiliation: Department of Internal Medicine II, University Hospital Würzburg, Würzburg University, 97080 Würzburg, Germany Center for Interdisciplinary Clinical Research, Würzburg University, 97080 Würzburg, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Winter
authors.affiliation: Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, Würzburg University, 97080 Würzburg, Germany.
authors.forename: Viktoria
authors.identifier: 0000-0002-5260-651X
authors.initials: V
authors.lastname: Schäfer
authors.affiliation: Microbiology Institute, Clinical Microbiology, Immunology and Hygiene, University Hospital Erlangen and Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Krappmann
authors.affiliation: Department of Internal Medicine II, University Hospital Würzburg, Würzburg University, 97080 Würzburg, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Einsele
authors.affiliation: Department for Molecular Plant Physiology and Biophysics, Julius-von-Sachs Institute, Würzburg University, 97080 Würzburg, Germany.
authors.forename: Thomas D
authors.identifier: 0000-0003-1862-7357
authors.initials: TD
authors.lastname: Müller
authors.affiliation: Institute for Virology and Research Center of Immunotherapy, University Medical Center of the Johannes Gutenberg-University, 55131 Mainz, Germany.
authors.forename: Matthias J
authors.initials: MJ
authors.lastname: Reddehase
authors.affiliation: Institute for Virology and Immunobiology, Würzburg University, 97080 Würzburg, Germany.
authors.forename: Manfred B
authors.initials: MB
authors.lastname: Lutz
authors.affiliation: Institute of Immunology, Regensburg University, 93053 Regensburg, Germany.
authors.forename: Daniela N
authors.identifier: 0000-0002-7571-4548
authors.initials: DN
authors.lastname: Männel
authors.affiliation: Department of Molecular Pathology, Institute of Pathology, Würzburg University, 97080 Würzburg, Germany.
authors.forename: Friederike
authors.identifier: 0000-0003-1673-4175
authors.initials: F
authors.lastname: Berberich-Siebelt
authors.affiliation: Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, Würzburg University, 97080 Würzburg, Germany beilhack_a@ukw.de harald.wajant@mail.uni-wuerzburg.de.
authors.forename: Harald
authors.identifier: 0000-0002-2005-3949
authors.initials: H
authors.lastname: Wajant
authors.affiliation: Department of Internal Medicine II, University Hospital Würzburg, Würzburg University, 97080 Würzburg, Germany Center for Interdisciplinary Clinical Research, Würzburg University, 97080 Würzburg, Germany Graduate School of Life Sciences, Würzburg University, 97080 Würzburg, Germany beilhack_a@ukw.de harald.wajant@mail.uni-wuerzburg.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Beilhack
mesh_terms: D000208:Acute Disease; D000818:Animals; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation; D007376:Interleukin-2 / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D000072737:Myeloid-Derived Suppressor Cells / Q000502:physiology; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D007376:Interleukin-2; D047889:Receptors, Tumor Necrosis Factor, Type II