Immune Tolerance Induced By Indoleamine 2,3-dioxygenase Gene Modified Bone Marrow Derived Dendritic Cells In Transplantation And Its Related Mechanisms

At present, organ transplantation becomes the preferred therapy for a lot of end-stage diseases. For the recent 50 years, it has achieved great success and brought improved life qualities to numerous patients. With the development of immunogenetics, we have increasing knowledge on immunological mechanisms underlying transplantation rejection. The application of CsA to clinic greatly reduced the morbidity of rejections. Nevertheless, clinical transplantation still faces some problems such as lifelong immunosupression associated with toxicity, opportunistic infection and a high incidence of cancer. Donor specific organ transplantation immune tolerance, being defined as no medication (only routine immunosuppressive agent), no rejection and no infection in MHC mismatched organ transplantation, is the trend of organ transplantation. Gene therapy techniques have great potential advantages according to the characteristic of organ transplantation. Although still in laboratory stage, it is a promising and practical scheme that immune tolerance can be induced by gene modified donor organ or recipient. Dendritic cells (DCs) play an important role in the strategies of tolerance induction.Dendritic cells (DCs), the most potent professional antigen presenting cells (APC), are very important in immune systems for their functions to activate naive T cells and initiate a primary immune response. Rejections induced by DCs may be donor-derived or recipient-derived. Donor-derived DCs called "passenger leukocytes" is the main factor in rejection for its direct function in activation of the host T cells. It has been recognized to be one of the most effective measures to prevent rejections by clearing away the "passenger leukocyte" from allografts. Recent studies have indicated that DCs may act as immune-stimulating cells as well as tolerance-inducing cells. There are immunophenotypical and functional changes in DCs during their maturation. DCs show strong tolerance-inducing activities immature stage, however, their characteristic turn to formidable immunogenicity after maturation. In 1992, Starzl et al found donor-derivedleukocytes residing in the blood, skin, and lymph nodes of recipients who carried their allo-heart or allo-liver over 30 years. This fact indicated that donor-derived stem cells survive in stage of microchimerism with host cells and may induce immune-tolerance or long-survival of allografts. It was further confirmed that both central and peripheral tolerance be induced by DCs which were the main components of donor-derived stem cells. In 1995, Lu L et al reported that immature DCs lacking costimulatory molecules, especially CD80 and CD86, could induce antigen-specific anergy in vitro. But in vivo, immature DCs become gradually mature, which could not maintenance tolerance. So we think if mature DCs were injected allogenic recipients, these could activate recipient's T cell. Making use of some kinds of routes to kill activated T cell , inducing tolerance. These make DCs an attractive candidate for tolerance induction and rejection prevention.Indoleamine 2,3-dioxygenase(IDO), a monomeric hemoprotein, is the initial and rate-limiting enzyme of the kynurenine pathway of degradation of L-tryptophan. This substance is further catabolized to terminal metabolites quinolinic acid. IDO oxidizes the pyrrole moiety of tryptophan. Following stimulation with IFN- r ,it is induced in various types of cell lines and cell types such as fibroblasts, epithelial cells and macrophages. High enzyme activity is present in the placenta, lung and small intestine. Tryptophan is necessary to the survival of some cell lines and pathogens, such as T cells.Recently, IDO has been implicated in the regulation of feto-maternal tolerance in a mouse model. Following the blocking of IDO by 1-methyl-tryptophan, allogeneic but not syngeneic fetuses were found to be rejected. This was provoked by a single(paternally inherited) MHC- I difference and depended on the activity of maternal T-cells. Application of 1-methyl-tryptophan resulted in...