Targeting Intestinal Permeability for Graft-versus-Host Disease Treatment: A Therapeutic Perspective with Defibrotide

Area of Science:

• Gastroenterology
• Immunology
• Pharmacology

Background:

• Acute graft-versus-host disease (aGVHD) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation.
• Intestinal barrier integrity loss is a key factor in aGVHD pathogenesis.
• Defibrotide, a heparin-like compound, is approved for severe veno-occlusive disease.

Purpose of the Study:

• To evaluate defibrotide's potential in restoring intestinal barrier integrity in aGVHD.
• To analyze the effect of defibrotide on tight junction proteins in an in vitro colon epithelium model.
• To assess defibrotide's impact on inflammatory cytokines in aGVHD patients' sera.

Main Methods:

• In vitro colon epithelium model treated with defibrotide under basal and inflammatory conditions.
• Immunocytochemical and Western blotting analysis of tight junction proteins (Zonulin-1, Occludin, Claudin-3).
• Multiplex analysis of 27 inflammatory cytokines in sera from two aGVHD patients before and after defibrotide treatment.

Main Results:

• Defibrotide significantly increased Zonulin-1 and Occludin expression in vitro.
• Defibrotide preserved Occludin and Claudin-3 levels under inflammatory conditions.
• Patients' sera showed altered cytokine profiles (e.g., IL-7, MIP-1β, IP-10) during acute aGVHD and remission after defibrotide treatment.

Conclusions:

• Defibrotide demonstrates potential in improving intestinal barrier integrity in aGVHD.
• Defibrotide may mitigate inflammation-related damage in the gut during aGVHD.
• Further investigation into defibrotide as a therapeutic agent for intestinal aGVHD is warranted.