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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.

SUBMITTER: Chopra M 

PROVIDER: S-EPMC4995078 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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

Chopra Martin M   Biehl Marlene M   Steinfatt Tim T   Brandl Andreas A   Kums Juliane J   Amich Jorge J   Vaeth Martin M   Kuen Janina J   Holtappels Rafaela R   Podlech Jürgen J   Mottok Anja A   Kraus Sabrina S   Jordán-Garrote Ana-Laura AL   Bäuerlein Carina A CA   Brede Christian C   Ribechini Eliana E   Fick Andrea A   Seher Axel A   Polz Johannes J   Ottmüller Katja J KJ   Baker Jeanette J   Nishikii Hidekazu H   Ritz Miriam M   Mattenheimer Katharina K   Schwinn Stefanie S   Winter Thorsten T   Schäfer Viktoria V   Krappmann Sven S   Einsele Hermann H   Müller Thomas D TD   Reddehase Matthias J MJ   Lutz Manfred B MB   Männel Daniela N DN   Berberich-Siebelt Friederike F   Wajant Harald H   Beilhack Andreas A  

The Journal of experimental medicine 20160815 9


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 (  ...[more]

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