| Allograft rejection is a serious problem to affect the survival time of grafts in organ transplantation.Up to now, systemic immunosuppressive medications are basically needed for every invalid who has accepted allograft, while long-term graft survival without immunosuppressant remains to be the Holy Grail of transplant physicians and immunologists.Dendritic cells (DCs), which are potent professional antigen presenting cells (APC) have appeared to be central to immune systems because of their abilities to prime naive T cells .and initiate a primary immune response. DCs resulting in rejections may be donor-derived or recipient-derived. Although the potent immunostimulatory capacity of DC is well recognized, recent evidence suggests that DC are also capable of inducing donor-specific hyporesponsiveness, It is not yet clear whether these apparently opposing functions of DC reflect distinct subpopulations of DC, or alternatively, distinct functionsexpressed at unique stages in the developmental cycle of the same cell.Recent studies have outlined that DCs may function as immune-stimulating cells as well as tolerance-inducing cells. DCs change immunophenotypically and functionally during their maturation. Immature DCs display tolerance-inducing activities, though they turn to exhibit their immunogenicity after maturation. This highlighted that tolerance to a vascularized allograft may be induced by microchimerism of donor cells, most of which were later found to be DCs. These findings furthered our impression that DCs may also have peripheral tolerance-inducing effect. In 1995, Lu L et al reported that immature DCs lackingcostimulatory molecules, especially CD80 and CD86, could induce antigen-specificanergy in vitro. There are now expanding evidences that immature DCs, after certain treatments, may be a promising method to improve the outcome of allograft transplantation. For example, adenoviral or retroviral delivery of cytotoxic T lymphocyte antigen-4Ig(CTLA-4Ig), Fas ligand, TGF- genes or viral interleukin-lO(vIL-lO) into myeloid DCs markedly inhibited their allostimulatory activities and led to much longer engraftmentOne molecule that may enhance the tolerance-inducing capacity of DC is FasLigand(FasL), a type II integral membrane protein that belongs to the TNF superfamily (10). Engagement of Fas by FasL initiates a signaling cascade that leads to apoptotic cell death of Fasbearing cells. Apoptosis induced by Fas/FasL interactions is thought to play a pivotal role in the immune system, regulating both peripheral T cell homeostasis and lymphocyte-mediated cytotoxicity. FasL is expressed in immunoprivileged organs, including the eye and testis, where it has been proposed to contribute to their tolerogenic milieu and paucity of infiltrating inflammatory cells. There is evidence that FasL constitutively expressed on splenic DC and bone marrow-derived DC may be involved in the killing of activated CD4+ T cells. More recently, tolerance induced by infusion of donor bone marrow cells was shown to be dependent on the expression of FasL on the infused cells. In the studies described below, we investigate the immunomodulatory effect of DC transduced to express high levels of FasL in vitro and in vivo.In our present research work., demonstrating that donor-derived mature DCs transferred with an adenoviral FasL construct, transfused to recipients before the surgery through the vein injection or. come to interestingly different results in a mouse vascularized heterotopic cardiac transplantation model. To investigate the mechanisms underlying the results obtained by infusion route, the immune functions and status of the recipients after i.v infusion of ad-FasL gene modified DCs were analyzed.PART I. The influence of Fas Ligand gene modification on the DC and allogeneic T Lymphocytic cellHigh-purity bone marrow-derived DCs were obtained to evaluate their morphological changes during their maturation. We found mature DCs distinguished from mature DCs in many aspects including morphology and function. Mature... |
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