title: Blocking TWEAK-Fn14 interaction inhibits hematopoietic stem cell transplantation-induced intestinal cell death and reduces GVHD.
abstract: Inhibition of the tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK)/fibroblast growth factor-inducible 14 (Fn14) system reduces intestinal cell death and disease development in several models of colitis. In view of the crucial role of TNF and intestinal cell death in graft-versus-host disease (GVHD) and the ability of TWEAK to enhance TNF-induced cell death, we tested here the therapeutic potential of Fn14 blockade on allogeneic hematopoietic cell transplantation (allo-HCT)-induced intestinal GVHD. An Fn14-specific blocking human immunoglobulin G1 antibody variant with compromised antibody-dependent cellular cytotoxicity (ADCC) activity strongly inhibited the severity of murine allo-HCT-induced GVHD. Treatment of the allo-HCT recipients with this monoclonal antibody reduced cell death of gastrointestinal cells but neither affected organ infiltration by donor T cells nor cytokine production. Fn14 blockade also inhibited intestinal cell death in mice challenged with TNF. This suggests that the protective effect of Fn14 blockade in allo-HCT is based on the protection of intestinal cells from TNF-induced apoptosis and not due to immune suppression. Importantly, Fn14 blockade showed no negative effect on graft-versus-leukemia/lymphoma (GVL) activity. Thus, ADCC-defective Fn14-blocking antibodies are not only possible novel GVL effect-sparing therapeutics for the treatment of GVHD but might also be useful for the treatment of other inflammatory bowel diseases where TNF-induced cell death is of relevance.
authors.affiliation: Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany; Center for Interdisciplinary Clinical Research, University of Würzburg, Würzburg, Germany;
authors.forename: Martin
authors.initials: M
authors.lastname: Chopra
authors.affiliation: Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany; Center for Interdisciplinary Clinical Research, University of Würzburg, Würzburg, Germany;
authors.forename: Andreas
authors.initials: A
authors.lastname: Brandl
authors.affiliation: Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany;
authors.forename: Daniela
authors.initials: D
authors.lastname: Siegmund
authors.affiliation: Institute of Pathology, University of Würzburg and Comprehensive Cancer Center Mainfranken, Würzburg, Germany;
authors.forename: Anja
authors.initials: A
authors.lastname: Mottok
authors.affiliation: Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany;
authors.forename: Viktoria
authors.initials: V
authors.lastname: Schäfer
authors.affiliation: Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany; Center for Interdisciplinary Clinical Research, University of Würzburg, Würzburg, Germany;
authors.forename: Marlene
authors.initials: M
authors.lastname: Biehl
authors.affiliation: Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany; Center for Interdisciplinary Clinical Research, University of Würzburg, Würzburg, Germany; Else-Kröner-Forschungskolleg Würzburg, Würzburg, Germany;
authors.forename: Sabrina
authors.initials: S
authors.lastname: Kraus
authors.affiliation: Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany; Center for Interdisciplinary Clinical Research, University of Würzburg, Würzburg, Germany;
authors.forename: Carina A
authors.initials: CA
authors.lastname: Bäuerlein
authors.affiliation: Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany; Center for Interdisciplinary Clinical Research, University of Würzburg, Würzburg, Germany;
authors.forename: Miriam
authors.initials: M
authors.lastname: Ritz
authors.affiliation: Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany; Center for Interdisciplinary Clinical Research, University of Würzburg, Würzburg, Germany;
authors.forename: Katharina
authors.initials: K
authors.lastname: Mattenheimer
authors.affiliation: Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany; Center for Interdisciplinary Clinical Research, University of Würzburg, Würzburg, Germany;
authors.forename: Stefanie
authors.initials: S
authors.lastname: Schwinn
authors.affiliation: Department of Oral and Maxillofacial Plastic Surgery, University Hospital Würzburg, Würzburg, Germany; and.
authors.forename: Axel
authors.initials: A
authors.lastname: Seher
authors.affiliation: Department of Biology, University of Konstanz, Konstanz, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Grabinger
authors.affiliation: Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany;
authors.forename: Hermann
authors.initials: H
authors.lastname: Einsele
authors.affiliation: Institute of Pathology, University of Würzburg and Comprehensive Cancer Center Mainfranken, Würzburg, Germany;
authors.forename: Andreas
authors.initials: A
authors.lastname: Rosenwald
authors.affiliation: Department of Biology, University of Konstanz, Konstanz, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Brunner
authors.affiliation: Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany; Center for Interdisciplinary Clinical Research, University of Würzburg, Würzburg, Germany; Else-Kröner-Forschungskolleg Würzburg, Würzburg, Germany;
authors.forename: Andreas
authors.initials: A
authors.lastname: Beilhack
authors.affiliation: Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany;
authors.forename: Harald
authors.initials: H
authors.lastname: Wajant
mesh_terms: D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use*; D000920:Antibody-Dependent Cell Cytotoxicity; D017209:Apoptosis; D015153:Blotting, Western; D002478:Cells, Cultured; D000074049:Cytokine TWEAK; D004195:Disease Models, Animal; D005260:Female; D005455:Fluorescent Antibody Technique; D006086:Graft vs Host Disease / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000276:immunology; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000276:immunology / Q000473:pathology*; D008163:Luminescent Measurements; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D017452:Receptors, IgG / Q000276:immunology / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000069283:Rituximab; D000074050:TWEAK Receptor; D000079424:Tumor Necrosis Factor Inhibitors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D048069:Tumor Necrosis Factors / Q000276:immunology / Q000378:metabolism
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D000074049:Cytokine TWEAK; C485701:Fcgr1 protein, mouse; D007074:Immunoglobulin G; D012333:RNA, Messenger; D017452:Receptors, IgG; D018124:Receptors, Tumor Necrosis Factor; C000613297:TNFRSF12A protein, human; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; C491645:Tnfsf12 protein, mouse; D000079424:Tumor Necrosis Factor Inhibitors; D014409:Tumor Necrosis Factor-alpha; D048069:Tumor Necrosis Factors; D000069283:Rituximab