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

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2015
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Chopra, Martin
Brandl, Andreas
Siegmund, Daniela
Mottok, Anja
Schäfer, Viktoria
Biehl, Marlene
Kraus, Sabrina
Bäuerlein, Carina A.
Ritz, Miriam
Mattenheimer, Katharina
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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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ISO 690CHOPRA, Martin, Andreas BRANDL, Daniela SIEGMUND, Anja MOTTOK, Viktoria SCHÄFER, Marlene BIEHL, Sabrina KRAUS, Carina A. BÄUERLEIN, Miriam RITZ, Katharina MATTENHEIMER, Stefanie SCHWINN, Axel SEHER, Thomas GRABINGER, Hermann EINSELE, Andreas ROSENWALD, Thomas BRUNNER, Andreas BEILHACK, Harald WAJANT, 2015. Blocking TWEAK-Fn14 interaction inhibits hematopoietic stem cell transplantation-induced intestinal cell death and reduces GVHD. In: Blood. 2015, 126(4), pp. 437-444. ISSN 0006-4971. eISSN 1528-0020. Available under: doi: 10.1182/blood-2015-01-620583
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@article{Chopra2015Block-32633,
  year={2015},
  doi={10.1182/blood-2015-01-620583},
  title={Blocking TWEAK-Fn14 interaction inhibits hematopoietic stem cell transplantation-induced intestinal cell death and reduces GVHD},
  number={4},
  volume={126},
  issn={0006-4971},
  journal={Blood},
  pages={437--444},
  author={Chopra, Martin and Brandl, Andreas and Siegmund, Daniela and Mottok, Anja and Schäfer, Viktoria and Biehl, Marlene and Kraus, Sabrina and Bäuerlein, Carina A. and Ritz, Miriam and Mattenheimer, Katharina and Schwinn, Stefanie and Seher, Axel and Grabinger, Thomas and Einsele, Hermann and Rosenwald, Andreas and Brunner, Thomas and Beilhack, Andreas and Wajant, Harald}
}
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