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Blocking TWEAK-Fn14 interaction inhibits hematopoietic stem cell transplantation-induced intestinal cell death and reduces GVHD.
Chopra, Martin; Brandl, Andreas; Siegmund, Daniela; Mottok, Anja; Schäfer, Viktoria; Biehl, Marlene; Kraus, Sabrina; Bäuerlein, Carina A; Ritz, Miriam; Mattenheimer, Katharina; Schwinn, Stefanie; Seher, Axel; Grabinger, Thomas; Einsele, Hermann; Rosenwald, Andreas; Brunner, Thomas; Beilhack, Andreas; Wajant, Harald.
Afiliación
  • Chopra M; Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany; Center for Interdisciplinary Clinical Research, University of Würzburg, Würzburg, Germany;
  • Brandl A; Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany; Center for Interdisciplinary Clinical Research, University of Würzburg, Würzburg, Germany;
  • Siegmund D; Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany;
  • Mottok A; Institute of Pathology, University of Würzburg and Comprehensive Cancer Center Mainfranken, Würzburg, Germany;
  • Schäfer V; Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany;
  • Biehl M; Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany; Center for Interdisciplinary Clinical Research, University of Würzburg, Würzburg, Germany;
  • Kraus S; 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;
  • Bäuerlein CA; Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany; Center for Interdisciplinary Clinical Research, University of Würzburg, Würzburg, Germany;
  • Ritz M; Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany; Center for Interdisciplinary Clinical Research, University of Würzburg, Würzburg, Germany;
  • Mattenheimer K; Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany; Center for Interdisciplinary Clinical Research, University of Würzburg, Würzburg, Germany;
  • Schwinn S; Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany; Center for Interdisciplinary Clinical Research, University of Würzburg, Würzburg, Germany;
  • Seher A; Department of Oral and Maxillofacial Plastic Surgery, University Hospital Würzburg, Würzburg, Germany; and.
  • Grabinger T; Department of Biology, University of Konstanz, Konstanz, Germany.
  • Einsele H; Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany;
  • Rosenwald A; Institute of Pathology, University of Würzburg and Comprehensive Cancer Center Mainfranken, Würzburg, Germany;
  • Brunner T; Department of Biology, University of Konstanz, Konstanz, Germany.
  • Beilhack A; 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;
  • Wajant H; Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany;
Blood ; 126(4): 437-44, 2015 Jul 23.
Article en En | MEDLINE | ID: mdl-26012567
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Apoptosis / Receptores del Factor de Necrosis Tumoral / Trasplante de Células Madre Hematopoyéticas / Anticuerpos Monoclonales de Origen Murino / Inhibidores del Factor de Necrosis Tumoral / Enfermedad Injerto contra Huésped / Intestinos Tipo de estudio: Etiology_studies / Prognostic_studies Idioma: En Revista: Blood Año: 2015 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Apoptosis / Receptores del Factor de Necrosis Tumoral / Trasplante de Células Madre Hematopoyéticas / Anticuerpos Monoclonales de Origen Murino / Inhibidores del Factor de Necrosis Tumoral / Enfermedad Injerto contra Huésped / Intestinos Tipo de estudio: Etiology_studies / Prognostic_studies Idioma: En Revista: Blood Año: 2015 Tipo del documento: Article Pais de publicación: Estados Unidos