TY - JOUR
T1 - The IL-33/ST2 axis augments effector T-cell responses during acute GVHD
AU - Reichenbach, Dawn K.
AU - Schwarze, Vincent
AU - Matta, Benjamin M.
AU - Tkachev, Victor
AU - Lieberknecht, Elisabeth
AU - Liu, Quan
AU - Koehn, Brent H.
AU - Pfeifer, Dietmar
AU - Taylor, Patricia A.
AU - Prinz, Gabriele
AU - Dierbach, Heide
AU - Stickel, Natalie
AU - Beck, Yvonne
AU - Warncke, Max
AU - Junt, Tobias
AU - Schmitt-Graeff, Annette
AU - Nakae, Susumu
AU - Follo, Marie
AU - Wertheimer, Tobias
AU - Schwab, Lukas
AU - Devlin, Jason
AU - Watkins, Simon C.
AU - Duyster, Justus
AU - Ferrara, James L.M.
AU - Turnquist, Heth R.
AU - Zeiser, Robert
AU - Blazar, Bruce R.
N1 - Publisher Copyright:
© 2015 by The American Society of Hematology.
PY - 2015
Y1 - 2015
N2 - 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-a 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-g production by st2-/- vs WT T cells during GVHD. Blockade of IL-33/ST2 interactions during allogeneic-hematopoietic celltransplantation byexogenousST2-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.
AB - 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-a 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-g production by st2-/- vs WT T cells during GVHD. Blockade of IL-33/ST2 interactions during allogeneic-hematopoietic celltransplantation byexogenousST2-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.
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U2 - 10.1182/blood-2014-10-606830
DO - 10.1182/blood-2014-10-606830
M3 - Article
C2 - 25814531
AN - SCOPUS:84943606387
SN - 0006-4971
VL - 125
SP - 3183
EP - 3192
JO - Blood
JF - Blood
IS - 20
ER -
