Blocking TWEAK-Fn14 interaction inhibits hematopoietic stem cell transplantation-induced intestinal cell death and
Martin Chopra1, Andreas Brandl1, Daniela Siegmund2
1Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany; Center for Interdisciplinary Clinical Research, University of Würzburg, Würzburg, Germany;
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.
Insights
Blocking the TWEAK/Fn14 pathway with an antibody reduced intestinal cell death in graft-versus-host disease (GVHD) models. This approach spares graft-versus-leukemia (GVL) activity, offering a potential therapy for GVHD and inflammatory bowel diseases.
Area of Science:
- Immunology
- Gastroenterology
- Oncology
Background:
- The TWEAK/Fn14 pathway plays a role in intestinal inflammation and cell death.
- Graft-versus-host disease (GVHD) involves TNF-induced intestinal cell death.
- Targeting TWEAK/Fn14 may offer therapeutic benefits in inflammatory conditions.
Purpose of the Study:
- To evaluate the therapeutic potential of Fn14 blockade in allogeneic hematopoietic cell transplantation (allo-HCT)-induced intestinal GVHD.
- To determine if Fn14 blockade affects immune suppression or graft-versus-leukemia (GVL) activity.
- To investigate the mechanism of Fn14 blockade in protecting intestinal cells.
Main Methods:
- Utilized an Fn14-specific blocking antibody with compromised ADCC activity in murine allo-HCT models.
- Assessed GVHD severity, gastrointestinal cell death, T cell infiltration, and cytokine production.
- Administered Fn14 blockade to mice challenged with TNF to study its effect on intestinal cell death.
Main Results:
- Fn14 blockade significantly inhibited the severity of murine allo-HCT-induced GVHD.
- Treatment reduced gastrointestinal cell death without affecting T cell infiltration or cytokine levels.
- Fn14 blockade protected intestinal cells from TNF-induced apoptosis and did not impair GVL activity.
Conclusions:
- ADCC-defective Fn14-blocking antibodies are effective in treating intestinal GVHD by protecting cells from TNF-induced apoptosis.
- This therapeutic strategy spares GVL activity, suggesting potential as a novel GVHD treatment.
- Fn14 blockade may also benefit other inflammatory bowel diseases involving TNF-induced cell death.
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