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

Acute graft-versus-host disease (aGVHD) is a significant cause of death in recipients of allogeneic hematopoietic stem cell transplantation. In this type of graft, the intestine is particularly affected, with the loss of intestinal barrier integrity playing a key role in its onset. In this scenario, the aim of the present research was to evaluate defibrotide, a heparin-like compound, marked for severe veno-occlusive disease, as an innovative therapeutic approach for restoring intestinal barrier integrity using an in vitro model and analyzing aGVHD patients' sera and clinical data.

Using an in vitro model of colon epithelium, we evaluated the modulation of tight junction proteins after defibrotide treatment, in basal condition or in presence of an inflammatory stimulus, by immunocytochemical and Western blotting analysis. Moreover, the study involved two patients with grade IV acute multisystem GVHD with great gastrointestinal compromission. Patients' sera were collected during the acute phase and remission of intestinal aGVHD and employed for the evaluation of a panel of 27 inflammatory cytokines using a Multiplex approach.

Defibrotide treatment significantly increased the protein expression of Zonulin-1 and Occludin (untreated vs treated with 200 μg/mL, p<0.01). In culture conditions mimicking inflammation, defibrotide countered the reduction of Occludin and Claudin-3 while preserving Zonulin-1 levels. Serum cytokine analysis of two patients receiving defibrotide for aGVHD showed significantly higher cytokine levels (IL-7, MIP-1β, IP-10, G-CSF, Eotaxin, IL-6) during the acute phase compared to remission after defibrotide treatment.

These findings suggest a potential therapeutic role for defibrotide in managing intestinal aGVHD by improving epithelial barrier integrity and reducing inflammation-related damage.