TY  - JOUR
A1  - Chopra, Martin
A1  - Biehl, Marlene
A1  - Steinfatt, Tim
A1  - Brandl, Andreas
A1  - Kums, Juliane
A1  - Amich, Jorge
A1  - Vaeth, Martin
A1  - Kuen, Janina
A1  - Holtappels, Rafaela
A1  - Podlech, Jürgen
A1  - Mottok, Anja
A1  - Kraus, Sabrina
A1  - Jordán-Garotte, Ana-Laura
A1  - Bäuerlein, Carina A.
A1  - Brede, Christian
A1  - Ribechini, Eliana
A1  - Fick, Andrea
A1  - Seher, Axel
A1  - Polz, Johannes
A1  - Ottmueller, Katja J.
A1  - Baker, Jeannette
A1  - Nishikii, Hidekazu
A1  - Ritz, Miriam
A1  - Mattenheimer, Katharina
A1  - Schwinn, Stefanie
A1  - Winter, Thorsten
A1  - Schäfer, Viktoria
A1  - Krappmann, Sven
A1  - Einsele, Hermann
A1  - Müller, Thomas D.
A1  - Reddehase, Matthias J.
A1  - Lutz, Manfred B.
A1  - Männel, Daniela N.
A1  - Berberich-Siebelt, Friederike
A1  - Wajant, Harald
A1  - Beilhack, Andreas
T1  - Exogenous TNFR2 activation protects from acute GvHD via host T reg cell expansion
JF  - Journal of Experimental Medicine
N2  - 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.
KW  - Tumor-necrosis-factor
KW  - Regulatory-cells
KW  - Bone marrow transplantantation
KW  - Graft-versus-leukemia
KW  - Rheumatoid arthritis
KW  - Autoimmune diseases
KW  - Factor receptor
KW  - Alpha therapy
KW  - Expression
KW  - Suppression
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-187640
VL  - 213
IS  - 9
ER  - 
TY  - JOUR
A1  - Schmid, Tobias
A1  - Falter, Lena
A1  - Weber, Sabine
A1  - Müller, Nils
A1  - Molitor, Konstantin
A1  - Zeller, David
A1  - Weber-Steffens, Dorothea
A1  - Hehlgans, Thomas
A1  - Wajant, Harald
A1  - Mostböck, Sven
A1  - Männel, Daniela N.
T1  - Chronic inflammation increases the sensitivity of mouse Treg for TNFR2 costimulation
JF  - Frontiers in Immunology
N2  - TNF receptor type 2 (TNFR2) has gained attention as a costimulatory receptor for T cells and as critical factor for the development of regulatory T cells (Treg) and myeloid suppressor cells. Using the TNFR2-specific agonist TNCscTNF80, direct effects of TNFR2 activation on myeloid cells and T cells were investigated in mice. \(In\) \(vitro\), TNCscTNF80 induced T cell proliferation in a costimulatory fashion, and also supported \(in\) \(vitro\) expansion of Treg cells. In addition, activation of TNFR2 retarded differentiation of bone marrow-derived immature myeloid cells in culture and reduced their suppressor function. \(In\) \(vivo\) application of TNCscTNF80-induced mild myelopoiesis in naïve mice without affecting the immune cell composition. Already a single application expanded Treg cells and improved suppression of CD4 T cells in mice with chronic inflammation. By contrast, multiple applications of the TNFR2 agonist were required to expand Treg cells in naïve mice. Improved suppression of T cell proliferation depended on expression of TNFR2 by T cells in mice repeatedly treated with TNCscTNF80, without a major contribution of TNFR2 on myeloid cells. Thus, TNFR2 activation on T cells in naïve mice can lead to immune suppression \(in\) \(vivo\). These findings support the important role of TNFR2 for Treg cells in immune regulation.
KW  - molecular medicine
KW  - inflammation
KW  - immune regulation
KW  - costimulation
KW  - MDSC
KW  - TNFR2
KW  - regulatory T cell
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173259
VL  - 8
ER  -