EBMT 2019 | Endothelial protection in steroid-refractory GvHD

Endothelial damage in target organs such as the colon, the liver and skin, as a consequence of steroid-refractory graft-versus-host disease (SR GvHD), has been suspected to increase mortality.¹ The protection of intestinal organs from endothelial damage may provide a novel approach in order to improve the survival rates of patients with SR GvHD.

On 27 March 2019, at the 45^th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT), Dr. Olaf Penack, from Charité Univerisätsmedizin Berlin, Berlin, DE, discussed endothelial damage and protection of the endothelium in SR GvHD, including assessment of a non-immunosuppressive approach, utilizing the phosphodiesterase type 5 inhibitor, sildenafil.²

Methods:

• Intestinal biopsy samples taken from patients following allogeneic hematopoietic stem cell transplantation (allo-HSCT)
• Murine models of acute GvHD (aGvHD), treated with or without steroids:
  • Balb/c mice transplanted with stem cells derived from B6 mice
  • B6 mice transplanted with stem cells derived from BDF mice
  • LP/J mice transplanted with stem cells derived from B6 mice
• Assays performed:
  • Immunostaining
  • Electron microscopy
  • Light sheet fluorescence microscopy (LSFM)
  • Fluorescence-activated cell sorting (FACS)
  • Assessment of endothelial dysfunction
• In models of SR GvHD, efficacy and safety of the phosphodiesterase type 5 inhibitor, sildenafil, was examined

Key findings:

• From patient biopsies, a significantly higher percentage of apoptotic vessels from the duodenum and colonic mucosa were found in patients with grade III-IV aGvHD compared to patients without GvHD

Murine models

• In a model of aGvHD, severe microstructural endothelial damage was detected
• During aGvHD, increased vessel branching and segmentation was seen following allo-HSCT
• In aGvHD, a significant reduction of intestinal pericyte coverage was identified after allo-HSCT
• Similarly, a reduction in tight and adhesion cell-cell contact molecules were seen in the post allo-SCT setting
• From a model of aGvHD, vascular leakiness was shown to increase in intestinal target organs but this trend was not seen in non-target organs such as kidney and muscle
• In intestinal SR GvHD, low inflammatory infiltration was identified, compared to untreated GvHD, in the presence of endothelial damage

Efficacy of in vitro sildenafil

• In murine models of aGvHD, treatment with sildenafil without steroid treatment improved survival following transplantation (P = 0.1040)
• In murine models of SR aGvHD, subsequent to transplantation, treatment with sildenafil significantly improved survival

Dr. Penack concluded that following allo-HSCT, the role of the endothelium in aGvHD is important to consider, with the results demonstrating that utilization of sildenafil as a non-immunosuppressive endothelial-protection treatment approach may improve outcomes in SR GvHD. These findings will need further validation, however, this supports the development of endothelial-targeted approaches for the treatment of SR GvHD.