Dissertation > Medicine, health > Pharmacy > Pharmacology

Regulation of Interaction between Endothelial Cell and T Lymphocytes by Fluvastatin and Its Signaling Mechanisms

Author WuLiHua
Tutor ZhengShuSen
School Zhejiang University
Course Surgery
Keywords Fluvastatin cyclosporin A EaHy926 cells T lymphocyte cells activation cells proliferation cytokine chemokine NF- k b nuclear transcription factor of activated T lymphocytes Pyk2 Vav
Type PhD thesis
Year 2005
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IntroductionWith the use of new and selective powerful immunosuppressive drugs, such as cyclosporine A (CsA) and tacrolimus(FK506), improvements in the understanding of immunology of transplantation, and progress in tissue typing, organ preservation and surgical technique, acute rejection episodes and short-term graft and patient survival rates have significantly improved in solid organ transplantation. However, no substantial progress has been made in the long-term patient survival rates. Chronic rejection, also named chronic graft dysfunction, accounts for the majority of graft losses. The pathogenesis involves chronic allograft vasculopathy (graft arteriosclerosis) and parenchymal fibrosis, which are the two predominant histologic features of chronic rejection.Recent findings demonstrate the pivotal role of endothelium in the development of graft arteriosclerosis. The endothelial cell layer that lines the vasculature feeding an allograft represents the initial contact site between immune system and the transplanted organ. The initiating injury is probabaly endothelial in origin. Endothelial cells (EC) express MHC-I and MHC-II, and endothelial cell antigens. Upon recognition of endothelial cell antigens, circulating T cells and macrophages infiltrate the endothelium and release a myriad of cytokines, which in turn result in further activation, increasing the expression of endothelial cell antigens, adhesionmolecules and chemokines, promoting T cells migration into the graft, and facilliating the subsequent recognition and destruction of parenchymal cells. Recurrent activation, injury, proliferation and repair of EC result in release of pro-fibrotic cytokines, recruitment of circulating leucocytes, proliferation of vascular smooth muscule cells, and deposition of extracellular matrix proteins, and ultimately encroachment of vasculature and graft loss.Furthermore, EC can activate resting CD4+ T cells in culture and provide signals resulting in T cell resistance to CsA, that is, EC-derived signals render T cell cytokine synthesis resistant to CsA. This may be important in the setting of graft arteriosclerosis occured in the presence of continued administration of CsA to patient, which appears to be driven by chronic immune inflammation, involving EC activation of CD4+ memory T cells. Interestingly, in search for signaling from EC during their interaction with activated T cells in the presence of CsA, CXC chemokines expression by EC was found to be resistant to suppression by CsA. Thus, by the expression of CXC chemokines, EC not only play an active role in recruitment of activated T lymphocytes from the blood stream into the transplanted organ by a multi-step process including rolling, firm adhesion, diapedesis and transmigration, but also contribute to ongoing CsA-resistant T cell activation, playing a major role in chronic graft rejection. Though the triggering mechanism of T cell activation by CXC chemokines is poorly understood, inhibition of EC-derived signaling to affect T cell activation may have profound consequence on graft survival.Due to dyslipidaemia primarily resulted from immunosuppressive drug treatment, statins are commonly used in solid organ transplantation recipients. Furthermore, some clinical transplantation studies have indicated the benefits of statins, which may be independent of their cholesterol-lowering effects. Results from the Assessment of Lescol in Renal Transplantation (ALERT) study demonstrated that fluvastatin therapy was associated with reduced cardiac events in kidney transplant patients without increasing the risk of side effects, such as musculoskeletal toxicity, malignancies, infections and drug interaction. Postoperative therapy with simvastatininitiated early after heart transplantation led to significantly better 8-year survival rates and a significantly lower incidence of transplant vasculopathy without impairment of organ function or severe adverse effects. The so-called pleiotropic or noncholesterol - lowering effects of statins have been gaining increasing attention. H

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