Impact of Different Immunosuppresive Drugs on the Endothelium. Protective Effect of Defibrotide

Abstract 5319

Endothelial dysfunction is a key factor in the development of hematopoietic stem cell transplantation (HSCT) complications due largely to the conditioning treatments. The effect of immunosuppressive therapy on endothelial function has not been explored in detail in this setting. We evaluated the effect of three immunosuppressive drugs: two calcineurin inhibitors (cyclosporine and tacrolimus) and an inhibitor of mTOR (rapamycin). Microvascular endothelial cells (HMEC) were exposed to the three drugs to assess changes in ICAM-1 expression on the cell surface, the reactivity of the extracellular matrix (ECM) generated, and in signaling proteins. Studies were conducted in the absence and presence of defibrotide (DF) to assess its protective effect. Only the exposure of HMEC to cyclosporine (CyA) increased significantly the expression of ICAM-1 (4-fold, p<0.01) and the reactivity of the ECM (surface covered by platelets of 32.1±2.6% vs. 26.5±2.5%, p<0.01). While tacrolimus itself only increased slightly ICAM-1 expression, rapamycin moderately decreased the ECM reactivity. Those changes due to CyA were prevented by DF. CyA induced the activation of AKT and Raf, among others, whose expression was inversely related (4- and 0.5-fold, respectively, with respect to control cells). DF reversed this trend (0.4- and 2.7-fold, respectively, with respect to CyA treated cells). In conclusion, both calcineurin inhibitors showed a proinflammatory effect, though only CyA exhibited significant proinflammatory and prothrombotic effects on the endothelium that correlated with AKT/Raf pathway activation. Interestingly, the protective anti-inflammatory and anti-thrombotic effect of defibrotide seems to occur through the same signaling pathway. In contrast, rapamycin did not exert any significant action on endothelium.