Tissue Factor in Transplantation -aspects on expression and inhibition

University dissertation from Department of Nephrology and Transplantation

Abstract: Organ transplantation provides a treatment of end-stage disease primarily in the kidney, liver and heart. The immunosuppressive treatment regimens of today efficiently prevent early acute rejection; however the long-term survival has not improved to the same extent. Within months/years the majority of transplanted organs develop chronic allograft dysfunction (CAD), associated with fibrosis and intimal hyperplasia. Both alloantigen-dependent and -independent factors are suspected to affect the deteriorative process. Among the latter are ischemia and reperfusion (I/R) injury and also drug-induced nephrotoxicity. Tissue factor (TF) is the principal initiator of blood coagulation and triggers the coagulation cascade upon complex formation with FVIIa. TF is normally not expressed on cells in contact with blood, but can be induced as a response to a multitude of stimuli. Among those, many are associated with events occurring at transplantation, such as hypoxia and I/R injury. TF has also been implicated as a mediator of cellular adhesion, migration and proliferation, which are important features of vascular remodelling during CAD. By employing an isogenic aortic transplant model in the rat, the role of TF for development of intimal hyperplasia caused by long cold ischemia, was studied. Inhibition of TF reduced formation of neo-intima in treated animals as compared to controls. TF was further studied as a potential chemo-attractant for smooth muscle cells, monocytes and also endothelial precursor cells. Allthree cell types migrated towards TF in a migration assay. With the aim to decrease the pro-thrombotic and inflammatory properties of activated endothelium, RNA interference was used to down-regulate TF expression in these cells. The total antigen content and also TF expression on the cell surface were diminished, however this did not result in a decreased catalytic activity of TF/FVIIa. Efficient TF reduction was reflected in morphological alterations and decreased cell viability. Additionally we studied the presence of TF antigen in human renal allografts afflicted by rejection or cyclosporin (CsA) nephrotoxicity. Grafts with acute CsA nephrotoxicity displayed a marked TF staining in the tubular brush border, significantly increased in terms of intensity and spread, compared to allografts undergoing acute rejection. Vascular endothelial staining was present in grafts afflicted by chronic vasculopaty as well as chronic CsA nephrotoxicity. The results of these studies collectively imply that TF acts as a mediator in processes associated with chronic vascular remodelling after transplantation. Furthermore, TF may be used as a histological marker for acute CsA nephrotoxicity, a condition which is difficult to diagnose in a straightforward manner.

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