• Dawn K Reichenbach, Vincent Schwarze, Benjamin M Matta, Victor Tkachev, Elisabeth Lieberknecht, Quan Liu, Brent H Koehn, Dietmar Pfeifer, Patricia A Taylor, Gabriele Prinz, Heide Dierbach, Natalie Stickel, Yvonne Beck, Max Warncke, Tobias Junt, Annette Schmitt-Graeff, Susumu Nakae, Marie Follo, Tobias Wertheimer, Lukas Schwab, Jason Devlin, Simon C Watkins, Justus Duyster, James L M Ferrara, Heth R Turnquist, Robert Zeiser, and Bruce R Blazar.
• Department of Pediatrics, Division of Hematology, Oncology, and Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN;
• Blood. 2015 May 14; 125 (20): 3183-92.

AbstractInterleukin (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.© 2015 by The American Society of Hematology.

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