A new potent approach to treat steroid-refractory acute Graft-versus-Host Disease?

Clinical studies suggested that endothelial dysfunction and damage can be involved in the development and severity of acute graft-versus-host disease (aGvHD), a complication in patients undergoing allogeneic hematopoietic cell transplantation. In a new paper under the lead of Olaf Penack from the Charité Berlin we show extensive damage, structural changes, and dysfunction of the vasculature during aGvHD. Subsequently, therapeutic intervention with an already clinical approved endothelium-protecting agent improved outcome in a mouse model of steroid-refractory aGvHD.

Allogeneic hematopoietic stem transplantation (allo-HCT) is the only curative treatment option for many patients suffering from blood cancers. However, there are still risks for patients undergoing allo-HCT. One major complication is acute graft-versus-host disease (aGvHD) occuring in more than two thirds of patients. This inflammatory condition primarily affecting the skin, liver, and intestines. Although treatment with steroids is successful in most patients, about the 20%-25% of patients fail initial steroid treatment resulting in a very high mortality rate. Currently, no standard treatment for this steroid-refractory aGVHD is available and its pathobiology remains poorly understood, thereby hindering the development of novel therapeutic approaches.

The endothelium is the first contact for immunological effector cells in the blood and a key regulator in various inflammatory processes. The endothelium was shown to be relevant for early complications after allo-HCT such as transplantation-associated-microangiopathy, veno-occlusive disease, capillary leak syndrome and diffuse alveolar hemorrhage. Recent studies also suggested a critical role of the endothelium in aGvHD. Accordingly, we found increased percentage of apoptotic Casp3⁺ blood vessels in duodenal and colonic mucosa biopsies of patients with severe aGvHD. 

In mouse models of experimental aGvHD, we detected severe microstructural endothelial damage and reduced endothelial pericyte coverage accompanied by reduced expression of endothelial tight junction proteins leading to increased endothelial leakage in aGvHD target organs. Employing light-sheet fluorescence microscopy revealed structural changes in the colonic vasculature including increased vessel branching and vessel diameter. Human biopsies and murine tissues from steroid refractory aGvHD revealed extensive tissue damage but low levels of alloreactive T cell infiltration in target organs, providing the rationale for T-cell independent steroid refractory aGvHD treatment strategies. Consequently, we tested the endothelium-protective PDE5 inhibitor sildenafil, which reduced apoptosis and improved metabolic activity of endothelial cells in vitro. Accordingly, sildenafil treatment improved survival and reduced target organ damage during experimental steroid refractory aGvHD. The study by Steffen Cordes et al. demonstrates extensive damage, structural changes, and dysfunction of the vasculature during aGvHD. Consequently, therapeutic intervention by endothelium-protecting agents, such as sildenafil, appear attractive to treat steroid refractory aGvHD complementing current anti-inflammatory treatment options. 

 

This work resulted from a strong collaborative effort between clinicians and scientists from different European medical centers: The Charité Berlin and the University Hospitals of Barcelona (Spain), Hannover, Heidelberg and Würzburg. Our lab was supported for this study be the DFG collaborative research center TRR221 GvH-GvL (project B11).

 

Reference:

Cordes S, Mokhtari Z, Bartosova M, Mertlitz S, Riesner K, Shi Y, Mengwasser J, Kalupa M, McGeary A, Schleifenbaum J, Schrezenmeier J, Bullinger L, Diaz-Ricart M, Palomo M, Carrreras E, Beutel G, Schmitt CP, Beilhack A, Penack O. (2021). Endothelial damage and dysfunction in acute graft-versus-host disease. Haematologica 106(8):2147-2160.