Blocking TWEAK-Fn14 interaction inhibits hematopoietic stem cell transplantation-induced intestinal cell death and reduces GVHD

Blood. 2015 Jul 23;126(4):437-44. doi: 10.1182/blood-2015-01-620583. Epub 2015 May 26.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal, Murine-Derived / therapeutic use*
  • Antibody-Dependent Cell Cytotoxicity
  • Apoptosis*
  • Blotting, Western
  • Cells, Cultured
  • Cytokine TWEAK
  • Disease Models, Animal
  • Female
  • Fluorescent Antibody Technique
  • Graft vs Host Disease / etiology
  • Graft vs Host Disease / metabolism
  • Graft vs Host Disease / pathology
  • Graft vs Host Disease / prevention & control*
  • Hematopoietic Stem Cell Transplantation / adverse effects*
  • Humans
  • Immunoglobulin G / administration & dosage
  • Immunoglobulin G / immunology
  • Intestinal Mucosa / metabolism
  • Intestines / immunology
  • Intestines / pathology*
  • Luminescent Measurements
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Receptors, IgG / immunology
  • Receptors, IgG / metabolism
  • Receptors, Tumor Necrosis Factor / antagonists & inhibitors*
  • Receptors, Tumor Necrosis Factor / genetics
  • Receptors, Tumor Necrosis Factor / immunology
  • Receptors, Tumor Necrosis Factor / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Rituximab
  • TWEAK Receptor
  • Tumor Necrosis Factor Inhibitors*
  • Tumor Necrosis Factor-alpha / pharmacology
  • Tumor Necrosis Factors / immunology
  • Tumor Necrosis Factors / metabolism

Substances

  • Antibodies, Monoclonal, Murine-Derived
  • Cytokine TWEAK
  • Fcgr1 protein, mouse
  • Immunoglobulin G
  • RNA, Messenger
  • Receptors, IgG
  • Receptors, Tumor Necrosis Factor
  • TNFRSF12A protein, human
  • TWEAK Receptor
  • Tnfrsf12a protein, mouse
  • Tnfsf12 protein, mouse
  • Tumor Necrosis Factor Inhibitors
  • Tumor Necrosis Factor-alpha
  • Tumor Necrosis Factors
  • Rituximab