Exogenous TNFR2 activation protects from acute GvHD via host T reg cell expansion

Author:

Chopra Martin12,Biehl Marlene12ORCID,Steinfatt Tim123ORCID,Brandl Andreas12,Kums Juliane4ORCID,Amich Jorge12,Vaeth Martin5ORCID,Kuen Janina5ORCID,Holtappels Rafaela6ORCID,Podlech Jürgen6ORCID,Mottok Anja7,Kraus Sabrina12ORCID,Jordán-Garrote Ana-Laura123,Bäuerlein Carina A.123,Brede Christian123,Ribechini Eliana8,Fick Andrea4,Seher Axel4ORCID,Polz Johannes9,Ottmüller Katja J.123ORCID,Baker Jeanette10ORCID,Nishikii Hidekazu10,Ritz Miriam12ORCID,Mattenheimer Katharina12,Schwinn Stefanie12,Winter Thorsten12,Schäfer Viktoria4ORCID,Krappmann Sven11,Einsele Hermann1,Müller Thomas D.12ORCID,Reddehase Matthias J.6,Lutz Manfred B.8,Männel Daniela N.9ORCID,Berberich-Siebelt Friederike5ORCID,Wajant Harald4ORCID,Beilhack Andreas123

Affiliation:

1. Department of Internal Medicine II, University Hospital Würzburg, Würzburg University, 97080 Würzburg, Germany

2. Center for Interdisciplinary Clinical Research, Würzburg University, 97080 Würzburg, Germany

3. Graduate School of Life Sciences, Würzburg University, 97080 Würzburg, Germany

4. Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, Würzburg University, 97080 Würzburg, Germany

5. Department of Molecular Pathology, Institute of Pathology, Würzburg University, 97080 Würzburg, Germany

6. Institute for Virology and Research Center of Immunotherapy, University Medical Center of the Johannes Gutenberg-University, 55131 Mainz, Germany

7. Institute of Pathology, Würzburg University, 97080 Würzburg, Germany

8. Institute for Virology and Immunobiology, Würzburg University, 97080 Würzburg, Germany

9. Institute of Immunology, Regensburg University, 93053 Regensburg, Germany

10. Blood and Marrow Transplantation, Stanford University School of Medicine, Stanford, CA 94305

11. Microbiology Institute, Clinical Microbiology, Immunology and Hygiene, University Hospital Erlangen and Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany

12. Department for Molecular Plant Physiology and Biophysics, Julius-von-Sachs Institute, Würzburg University, 97080 Würzburg, Germany

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.

Funder

Johannes Gutenberg University, Mainz

José Carreras Leukämie-Stiftung

Else-Kröner-Fresenius-Stiftung

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

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