The IL-33/ST2 axis augments effector T-cell responses during acute GVHD

DK Reichenbach, V Schwarze, BM Matta… - Blood, The Journal …, 2015 - ashpublications.org
DK Reichenbach, V Schwarze, BM Matta, V Tkachev, E Lieberknecht, Q Liu, BH Koehn
Blood, The Journal of the American Society of Hematology, 2015ashpublications.org
Abstract 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 …
Abstract
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.
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