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Protection Of Calcitriol On Allograft From Acute Rejection Following Rat Orthotopic Liver Transplantation And Its Mechanism

Posted on:2006-11-23Degree:DoctorType:Dissertation
Country:ChinaCandidate:A B ZhangFull Text:PDF
GTID:1104360152993168Subject:Surgery
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IntroductionRecently, with the progress in the surgical technique, preservation method of the graft and the clinical application of immunosuppressive agent, survivals of recipients after liver transplantation have been improved significantly. However, the acute rejection which is mediated by cell immune is still the main obstacle which influences the result of transplantation. It was reported that the morbidity of acute rejection is about 40%~70%, and it will result in a part of grafts lose their function. The main clinical means at present to inhibit acute rejection is nonspecial immunosuppressant therapy. Those immunosuppressants can inhibit the function of immunol system entirely. It will increase the risk of suffering from infection and tumor. So, it always was focused in the transplantation domain to explore a new immunosuppressant which can inhibit acute rejection of allograft.Calcitriol is the active metabolite of the vitamin D. It is an endogenesis hormone that is the key regulator of calcium calcium, phosphorus, and bone metabolism. Pevious study has demonstrated that calcitriol has comprehensive immunoregulation effect. It has been demonstrated that the VDR appear in a wide variety of immunoactive cell such asthymocyte, promyelocyte and mononuclear cell, macrophage, activated T lymphocyte in peripheral blood. Vitamin D functions as immunoactive agent through combining with VDR. Combination of calcitriol with VDR influences the activity of transcripition factor. As a consequence, transcription of target gene was inhibited or activated. The in vitro studies have demonstrated that calcitriol can inhibit directly the Th1-type T cell to secret cytokine such as IL-2, IFN-γ and TNF-a, and stimulate Th2-type T cell to secret cytokine such as IL-4, -5 and IL-10. Meanwhile, calcitriol can inhibit the secretion of IL-12 by B lymphocyte, resulting in the further regulation of T cell proliferation and activation. Other studies have suggested that calcitriol may interfere with antigen-presenting cell function by decreasing MHC class II expression and B7.1, B7.2 and CD40 molecular expression resulting in the inhibition of co-stimmulator pathway. Finally, calcitriol has been shown to inhibit both the generation of cytotoxic T lymphocytes and natural killer NK-mediated cytotoxicity in vitro. Recently, capacity of calcitriol in induction of tolerogenic dendritic cells and regulatory T cells has been documented.The immunoregulation effect of calcitriol in vivo has been investigated. Several studuies have demonstrated that calcitriol can prolong the graft survival whether to non-vacularized graft such as skin, or to vacularized graft such as cardiac and kidney, and would not result in the side-effect such as infection and bone lose which was frequent in the process of classical immunosuppressant treatment. However, some documents also have reported that calcitriol did not prolong survival of murine skin grafts. Thus, it seemed unclear whether calcitriol played any role in the rejection of allograft. The process of injuring to graft which is initiated by host immune system is complex. It is participated by several kinds of immunoactive cells and small molecular proteins. The proliferation and activation is the key step of this procedure. In allografting, the rest T cell is activated by the stimulator from alloantigen which is presented by Antigen Presenting Cell (APC). With co-opration of the co-stimulate signal, T cell synthesizes and secretes IL-2 and expresses IL-2 R a. Combinition of IL-2 and IL-2 Ra impels T cells into the stageof DNA synthesize, which will result in proliferation of T cell. The activated T cell subsequently differentiates into cytotoxic T lymphocyte (CTL) or T helper cell (Th). CTL can injury directly the target cell through perforin and granuenzyme B pathway and Fas/FasL pathway. With conduction of capase family and Bcl-2 family proteins in cytoplasm, the death signal from cell membranes is transmitted into nuclear. Chromosome is broken and apoptosis of target cell occur, which lead to dysfunction of gr...
Keywords/Search Tags:Calcitriol, Cyclosporine A, Orthotopic liver transplantation, T lymphocyte, Acute rejection, Apoptosis, Apoptosis-relative protein, Cytokine, Mixed lymphocyte reaction, Synergistic effect
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