Steroid-refractory GVHD: T-cell attack within a vulnerable endothelial system

Abstract

Acute graft-versus-host disease (GVHD) is a major complication of allogeneic stem cell transplantation (SCT) and can be readily controlled by systemic high-dose steroids in many patients. However, patients whose GVHD is refractory to this therapy have a poor prognosis. Refractory patients have ongoing end-organ damage despite effective immunosuppression with second-line regimens, suggesting pathomechanisms independent from the initiating T-cell attack. To explore whether endothelial damage might contribute to GVHD refractoriness and to study the role of angiopoietin-2 (ANG2) in this process, we have compared kinetics of T-cell activation markers and markers of endothelial dysfunction in the serum of patients with sensitive (n ‫؍‬ 23) and refractory GVHD (n ‫؍‬ 25). Longitudinal measurements of soluble FAS ligand along with other immune markers demonstrate that refractory patients are not exposed to an overwhelming or unresponsive Tcell attack. However, in contrast to sensitive GVHD, refractory GVHD was associated with rising thrombomodulin levels and high ANG2/ vascular endothelialderived growth factor ratios. Patients with refractory GVHD showed significantly increased ANG2 levels already before SCT. These results suggest that endothelial cell vulnerability and dysfunction, rather than refractory T-cell activity, drives treatment refractoriness of GVHD and opens new avenues for prediction and control of this devastating condition. (Blood. 2011; 118(6):1685-1692)

Higher angiopoietin-2 and VEGF levels predict shorter EFS and increased non-relapse mortality after pediatric hematopoietic SCT

“…Unfortunately, neither did they analyze pediatric patients separately nor state whether Ang2 was analyzed from plasma or serum. In a recent study of Luft et al,20 Ang2/VEGF was associated with steroid-refractory GVHD. According to their study, endothelial cell vulnerability and dysfunction, rather than refractory T-cell activity, drives treatment refractoriness of GVHD via Ang2, VEGF and thrombomodulin.…”

The Use of Hyperbaric Oxygen Therapy in the Treatment of Non-healing Ulcers Secondary to Graft-versus-host Disease

“…6 Along with this, there are multiple studies that examine endothelial activation markers in the post-BMT period including von Willebrand factor, thrombomodulin and Fas/Fas-ligand. 5,7,8 The mounting evidence of angiopathy associated with GvHD and BMT is even further displayed with more qualitative analysis of structural findings including vessel rarefication, neovascularization, endothelial microparticles and circulating endothelial cells. 5,[8][9][10] While the research demonstrates potential vascular damage directly associated with GvHD, the question as to a relationship to poor wound healing has received little to no attention.…”

Thrombomodulin alleviates murine GVHD in association with an increase in the proportion of regulatory T cells in the spleen

“…Recent studies suggested that vascular endothelial vulnerability and endothelial dysfunction are involved in the pathogenesis of GVHD. [11][12][13] Elevated pretransplant serum levels of angiopoietin-2, a hormone mediating vascular vulnerability, and nitrate are noted in steroidrefractory GVHD patients. 11,12 A marker of endothelial damage including soluble TM is elevated in patients with steroid-refractory GVHD.…”

“…[11][12][13] Elevated pretransplant serum levels of angiopoietin-2, a hormone mediating vascular vulnerability, and nitrate are noted in steroidrefractory GVHD patients. 11,12 A marker of endothelial damage including soluble TM is elevated in patients with steroid-refractory GVHD. 13 These observations encouraged us to hypothesize that the prophylactic use of rTM with cytoprotective as well as antiinflammatory activity would decrease the incidence of GVHD in transplant patients.…”