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Blocking TWEAK-Fn14 interaction inhibits hematopoietic stem cell transplantation-induced intestinal cell death and reduces GVHD
| العنوان: | Blocking TWEAK-Fn14 interaction inhibits hematopoietic stem cell transplantation-induced intestinal cell death and reduces GVHD |
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| المؤلفون: | 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 |
| المصدر: | Blood; July 2015, Vol. 126 Issue: 4 p437-444, 8p |
| مستخلص: | 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. |
| قاعدة البيانات: | Supplemental Index |
Full Text Finder | تدمد: | 00064971 15280020 |
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| DOI: | 10.1182/blood-2015-01-620583 |