title: The IL-33/ST2 axis augments effector T-cell responses during acute GVHD.
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.
authors: Department of Pediatrics, Division of Hematology, Oncology, and Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN;
authors: Dawn K
authors: http://orcid.org/0000-0002-3855-5541
authors: DK
authors: Reichenbach
authors: Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center Freiburg, Albert-Ludwigs-University of Freiburg, Freiburg, Germany;
authors: Vincent
authors: V
authors: Schwarze
authors: Thomas E. Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA;
authors: Benjamin M
authors: BM
authors: Matta
authors: Department of Pediatrics, Division of Hematology/Oncology, University of Michigan, Ann Arbor, MI;
authors: Victor
authors: V
authors: Tkachev
authors: Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center Freiburg, Albert-Ludwigs-University of Freiburg, Freiburg, Germany;
authors: Elisabeth
authors: E
authors: Lieberknecht
authors: Thomas E. Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA;
authors: Quan
authors: Q
authors: Liu
authors: Department of Pediatrics, Division of Hematology, Oncology, and Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN;
authors: Brent H
authors: BH
authors: Koehn
authors: Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center Freiburg, Albert-Ludwigs-University of Freiburg, Freiburg, Germany;
authors: Dietmar
authors: D
authors: Pfeifer
authors: Department of Pediatrics, Division of Hematology, Oncology, and Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN;
authors: Patricia A
authors: PA
authors: Taylor
authors: Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center Freiburg, Albert-Ludwigs-University of Freiburg, Freiburg, Germany;
authors: Gabriele
authors: G
authors: Prinz
authors: Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center Freiburg, Albert-Ludwigs-University of Freiburg, Freiburg, Germany;
authors: Heide
authors: H
authors: Dierbach
authors: Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center Freiburg, Albert-Ludwigs-University of Freiburg, Freiburg, Germany;
authors: Natalie
authors: N
authors: Stickel
authors: Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center Freiburg, Albert-Ludwigs-University of Freiburg, Freiburg, Germany;
authors: Yvonne
authors: Y
authors: Beck
authors: Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, Switzerland;
authors: Max
authors: M
authors: Warncke
authors: Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, Switzerland;
authors: Tobias
authors: T
authors: Junt
authors: Department of Pathology, University Medical Center Freiburg, Albert-Ludwigs-University of Freiburg, Freiburg, Germany;
authors: Annette
authors: A
authors: Schmitt-Graeff
authors: Frontier Research Initiative, Institute of Medical Sciences, University of Tokyo, Tokyo, Japan;
authors: Susumu
authors: S
authors: Nakae
authors: Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center Freiburg, Albert-Ludwigs-University of Freiburg, Freiburg, Germany;
authors: Marie
authors: M
authors: Follo
authors: Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center Freiburg, Albert-Ludwigs-University of Freiburg, Freiburg, Germany;
authors: Tobias
authors: T
authors: Wertheimer
authors: Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center Freiburg, Albert-Ludwigs-University of Freiburg, Freiburg, Germany;
authors: Lukas
authors: L
authors: Schwab
authors: Center for Biological Imaging and Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA;
authors: Jason
authors: J
authors: Devlin
authors: Center for Biological Imaging and Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA;
authors: Simon C
authors: SC
authors: Watkins
authors: Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center Freiburg, Albert-Ludwigs-University of Freiburg, Freiburg, Germany;
authors: Justus
authors: J
authors: Duyster
authors: Department of Pediatrics, Division of Hematology/Oncology, University of Michigan, Ann Arbor, MI;
authors: James L M
authors: JL
authors: Ferrara
authors: Thomas E. Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA; and.
authors: Heth R
authors: HR
authors: Turnquist
authors: Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center Freiburg, Albert-Ludwigs-University of Freiburg, Freiburg, Germany; Centre for Biological Signaling Studies BIOSS, Albert-Ludwigs-University of Freiburg, Freiburg, Germany.
authors: Robert
authors: R
authors: Zeiser
authors: Department of Pediatrics, Division of Hematology, Oncology, and Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN;
authors: Bruce R
authors: BR
authors: Blazar
mesh_terms: D000208:Acute Disease; D000818:Animals; D016000:Cluster Analysis; D004195:Disease Models, Animal; D015870:Gene Expression; D020869:Gene Expression Profiling; D006086:Graft vs Host Disease / Q000175:diagnosis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000401:mortality; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000473:pathology / Q000528:radiation effects; D007519:Isoantigens / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D012720:Severity of Illness Index; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D014019:Tissue Donors; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous
chemical_list: C079241:IL1RL1 protein, human; C506536:IL33 protein, human; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins; D007519:Isoantigens; D011956:Receptors, Cell Surface; D007371:Interferon-gamma