Reichenbach Dawn K, Schwarze Vincent, Matta Benjamin M, Tkachev Victor, Lieberknecht Elisabeth, Liu Quan, Koehn Brent H, Pfeifer Dietmar, Taylor Patricia A, Prinz Gabriele, Dierbach Heide, Stickel Natalie, Beck Yvonne, Warncke Max, Junt Tobias, Schmitt-Graeff Annette, Nakae Susumu, Follo Marie, Wertheimer Tobias, Schwab Lukas, Devlin Jason, Watkins Simon C, Duyster Justus, Ferrara James L M, Turnquist Heth R, Zeiser Robert, Blazar Bruce R
Department of Pediatrics, Division of Hematology, Oncology, and Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN;
Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center Freiburg, Albert-Ludwigs-University of Freiburg, Freiburg, Germany;
Blood. 2015 May 14;125(20):3183-92. doi: 10.1182/blood-2014-10-606830. Epub 2015 Mar 26.
Interleukin (IL)-33 binding to the receptor suppression of tumorigenicity 2 (ST2) produces pro-inflammatory and anti-inflammatory effects. Increased levels of soluble ST2 (sST2) are a biomarker for steroid-refractory graft-versus-host disease (GVHD) and mortality. However, whether sST2 has a role as an immune modulator or only as a biomarker during GVHD was unclear. We show increased IL-33 production by nonhematopoietic cells in the gastrointestinal (GI) tract in mice post-conditioning and patients during GVHD. Exogenous IL-33 administration during the peak inflammatory response worsened GVHD. Conversely, GVHD lethality and tumor necrosis factor-α production was significantly reduced in il33(-/-) recipients. ST2 was upregulated on murine and human alloreactive T cells and sST2 increased as experimental GVHD progressed. Concordantly, st2(-/-) vs wild-type (WT) donor T cells had a marked reduction in GVHD lethality and GI histopathology. Alloantigen-induced IL-18 receptor upregulation was lower in st2(-/-) T cells, and linked to reduced interferon-γ production by st2(-/-) vs WT T cells during GVHD. Blockade of IL-33/ST2 interactions during allogeneic-hematopoietic cell transplantation by exogenous ST2-Fc infusions had a marked reduction in GVHD lethality, indicating a role of ST2 as a decoy receptor modulating GVHD. Together, these studies point to the IL-33/ST2 axis as a novel and potent target for GVHD therapy.
白细胞介素（IL）-33与肿瘤抑制因子2（ST2）受体结合可产生促炎和抗炎作用。可溶性ST2（sST2）水平升高是类固醇难治性移植物抗宿主病（GVHD）和死亡率的生物标志物。然而，sST2在GVHD期间是作为免疫调节剂还是仅作为生物标志物尚不清楚。我们发现，预处理后的小鼠和GVHD患者胃肠道中的非造血细胞产生的IL-33增加。在炎症反应高峰期给予外源性IL-33会使GVHD恶化。相反，il33（-/-）受体的GVHD致死率和肿瘤坏死因子-α的产生显著降低。ST2在小鼠和人类同种异体反应性T细胞上上调，并且随着实验性GVHD的进展sST2增加。一致地，与野生型（WT）供体T细胞相比，st2（-/-）供体T细胞的GVHD致死率和胃肠道组织病理学显著降低。在GVHD期间，同种异体抗原诱导的IL-18受体上调在st2（-/-）T细胞中较低，并且与st2（-/-）与WT T细胞相比干扰素-γ产生减少有关。通过外源性ST2-Fc输注阻断同种异体造血细胞移植期间的IL-33/ST2相互作用可显著降低GVHD致死率，表明ST2作为调节GVHD的诱饵受体发挥作用。总之，这些研究表明IL-33/ST2轴是GVHD治疗的一个新的有效靶点。
