Exogenous TNFR2 activation protects from acute GvHD via host T reg cell expansion.
Exogenous TNFR2 activation protects from acute GvHD via host T reg cell expansion.
复制标题
DOI：
10.1084/jem.20151563
复制
发表时间：
2016-08-22
期刊：
影响因子：
--
通讯作者：
Beilhack A
中科院分区：
文献类型：
--
作者：
Chopra M;Biehl M;Steinfatt T;Brandl A;Kums J;Amich J;Vaeth M;Kuen J;Holtappels R;Podlech J;Mottok A;Kraus S;Jordán-Garrote AL;Bäuerlein CA;Brede C;Ribechini E;Fick A;Seher A;Polz J;Ottmüller KJ;Baker J;Nishikii H;Ritz M;Mattenheimer K;Schwinn S;Winter T;Schäfer V;Krappmann S;Einsele H;Müller TD;Reddehase MJ;Lutz MB;Männel DN;Berberich-Siebelt F;Wajant H;Beilhack A
用一种新的激动剂激活TNFR 2在体内扩增T reg细胞，并保护allo-HCT受体免受急性GvHD，同时保留移植供体T细胞的抗淋巴瘤和抗感染特性。供体CD 4 + Foxp 3+调节性T细胞（T reg细胞）抑制异基因造血干细胞移植（HCT [allo-HCT]）后的移植物抗宿主病（GvHD）。目前的临床研究方案依赖于供体T reg细胞的离体扩增及其大量输注。在这项研究中，我们提出了一种抑制GvHD的新策略，该策略基于在allo-HCT之前受体T reg细胞的体内扩增，利用肿瘤坏死因子受体2（TNFR 2）在T reg细胞生物学中的关键作用。在allo-HCT之前使用小鼠TNFR 2选择性激动剂在受体小鼠中扩增抗辐射的宿主T reg细胞以TNFR 2和T reg细胞依赖性方式显著延长存活并降低GvHD严重程度。移植的T细胞对白血病细胞和感染性病原体的有益作用不受影响。相应的人TNFR 2特异性激动剂在体外扩增人T reg细胞。这些观察结果表明，我们的策略通过在体内选择性TNFR 2活化扩增T reg细胞来保护allo-HCT患者免受急性GvHD的影响。
Activation of TNFR2 with a novel agonist expands T reg cells in vivo and protects allo-HCT recipients from acute GvHD while sparing antilymphoma and antiinfectious properties of transplanted donor T cells. 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.