CYCLOSPORINE-A INHIBITS MONOCYTE TISSUE FACTOR ACTIVATION IN CARDIAC TRANSPLANT RECIPIENTS

Background Fibrin deposition and thrombosis have been implicated in bo th allograft rejection and vasculopathy after cardiac transplantation, Because monocytes play a pivotal role in the pathophysiology of intra vascular coagulation activation through their ability to synthesize ti ssue factor (TF), we asked (1) whether monocyte TF activation occurs i n cardiac transplant recipients and (2) whether monocyte TF expression is affected by treatment with cyclosporin A (CsA). Methods and Result s We measured levels of TF activity in peripheral blood mononuclear ce lls and highly purified monocytes/macrophages from 10 consecutive card iac transplant recipients and 10 healthy control subjects. TF activity generated by bath unstimulated and endotoxin-stimulated cells was sig nificantly higher in transplant recipients than in control subjects (P <.05). Increased monocyte TF expression in transplant recipients was s hown to br adversely affected by treatment with CsA: TF Induction was markedly reduced by CsA serum concentrations reaching peak CsA drug le vels. Inhibition of TF induction in the presence of high CsA blood con centrations was also observed when stimulation of cells was performed with interferon-gamma or interleukin-1 beta. As shown by reverse trans cription-polymerase chain reaction and electrophoretic mobility shift assay, respectively, treatment with CsA leads to decreased TF mRNA exp ression and reduced activation of the NF-kappa B transcription factor, which is known to contribute to the induction of the TF promotor in h uman monocytes. Conclusions This study demonstrates that TF activation , occurring in mononuclear cells of cardiac transplant recipients, is inhibited by treatment with CsA. Inhibition of monocyte TF induction b y CsA may contribute to its successful use in cardiac transplant medic ine and might be useful in managing further settings of vascular patho logy also known to involve TF expression and NF-kappa B activation.