Loss of endothelial thrombomodulin predicts response to steroid therapy and survival in acute intestinal graft-versus-host disease

Abstract

Steroid-refractory graft-versus-host disease causes significant morbidity and mortality after allogeneic stem cell transplantation. The pathomechanism of steroid resistance is currently not understood, but it has been suggested that endothelial cell dysfunction plays a role. Endothelial thrombomodulin was quantified along with histological markers of epithelial damage and cytotoxic T cells in colon biopsies from 51 allografted patients, and retrospectively correlated with response to steroids and survival. Loss of endothelial thrombomodulin was the strongest predictor of response to steroids (P=0.02) and nonrelapse mortality (P=0.01) in multivariate analyses adjusting for T-cell infiltrates, histological grading, vessel density, disease status, donor type, and conditioning therapy. Our data provide evidence that at disease onset, loss of endothelial thrombomodulin expression rather than excessive T-cell infiltration associates with steroid-refractory graft-versus-host disease and mortality. Prospective histological investigations are now warranted to improve diagnosis and prognostication of this core complication of stem cell transplantation.

Figure 1.

Loss of endothelial thrombomodulin expression in colon mucosa of GvHD-patients predicts NRM and OS. Representative examples of eTM in colon biopsies taken for suspected GVHD after SCT (400x original magnification). Matched serial sections of the same biopsy immunostained for eTM (left column) and CD34 (right column). Case (A), all CD34+ vessels strongly express eTM (eTM intensity=3). Case (B), moderate eTM (eTM intensity=2). Case (C), loss of eTM expression on single endothelial cells resulting in patchy staining was judged as weak expression (eTM intensity=1). Case (D), absent expression (eTM intensity= 0) required at least 3 vessels completely negative for eTM staining (corresponding vessels in CD34 and eTM-stained sections marked by arrowheads). eTM-positive mucosal myofibroblasts served as internal control. (E and F) Univariate analyses of influence on (E) non-relapse mortality (NRM) and (F) overall survival (OS) following biopsy comparing patients categorized according to the eTM score (eTM score<2: black line, eTM score≥2: dashed line) evaluated before start of immunosuppressive treatment for GvHD. x axis: time (months) following biopsy.