Prevention Of Graft Versus Host Disease By Fas Ligand Expressing Dendritic Cells

FasL gene-modified dendritic cells alleviating GVHD Allogeneic bone marrow transplantation (alloBMT) has revolutionized thetreatment of hematopoietic malignancies, inherited hematopoietic disorders, andaplastic anemia. Unfortunately, Graft-versus-host disease (GVHD) is still a majorcomplication of allogeneic bone marrow transplantation (BMT) and results insignificant morbidity and mortality. Donor T lymphocytes in the BM or peripheralblood stem cell transplant cause GVHD by recognizing major as well as minorhistocompatibility antigens. Although innovative strategies for the prediction,prevention, and treatment of this caveat in allogeneic BMT have been proposed,prophylaxis or treatment of GVHD still remains unsatisfactory. Removal ofdonor-derived T lymphocytes prior to transplantation efficiently amelioratesGVHD. However, ex vivo depletion of T cells has been associated with anincreased risk of viral opportunistic infections, impaired engraftment, and the lossof the graft-versus-leukemia (GVL) effect, resulting in an increased incidence ofrecurrence of leukemia. Several clinical and experimental studies support the ideathat GVHD and GVL are mediated not only by the same (host-specific) T cell butalso by distinct (leukemia-specific) alloreactive donor T-cell populations.Moreover, allo-major histocompatibility complex (MHC)-restricted cytotoxic Tlymphocytes (CTLs) to antigens frequently expressed at elevated levels onleukemic cells can be cloned from an allorestricted T-cell repertoire and used tomediate a GVL reaction without causing GVHD. Dendritic cells (DC) are APC that play a critical role in the initiation ofimmune responses. Genetic modification of DC with genes encodingimmunoregulatory molecules is an alternative for artificial generation oftolerogenic DC. Indeed, recent reports suggest that transfection of DC with IL-10and TGF can increase their tolerogenic potential. Several attributes make DC ideal 5 第二军医大学硕士研究生论文Fas Ligand 基因修饰的树突状细胞抑制 GVHD 反应和机理vehicles for the delivery of such molecules. They are potent activators of naive Tcells, a function related to their Ag-processing capacity and to high levels ofexpression of MHC and costimulatory molecules. One molecule that may enhance the tolerance-inducing capacity of DC is Fasligand (FasL), a type II integral membrane protein that belongs to the TNFsuperfamily. Engagement of Fas by FasL initiates a signaling cascade that leads toapoptotic cell death of Fas-bearing cells. Apoptosis induced by Fas/FasLinteractions is thought to play a pivotal role in the immune system, regulating bothperipheral T cell homeostasis and lymphocyte-mediated cytotoxicity. FasL isexpressed in immunoprivileged organs, including the eye and testis, where it hasbeen proposed to contribute to their tolerogenic milieu and paucity of infiltratinginflammatory cells. There is evidence that FasL constitutively expressed on splenicDC and bone marrow-derived DC may be involved in the killing of activatedCD4+ T cells. Wei-ping Min et al have induced donor-specific hyporesponsivenessto alloantigen in vivo and prolong organ allograft survival with FasL-DC in murinemodel. The critical first step in the initiation of GVHD is antigen presentation todonor T cells by recipient (not donor) APCs. So we proposed that host bonemarrow-derived DC transduced to express FasL can deplete alloreactive cellsfrom donor haematopoietic stem cell grafts in vitro, and transplantation with thismanipulated grafts may prevent GVHD and keep GVL and antiviral immunityeffects. In this study we tested this approach by the induction of apoptosis in activatedalloreactive T lymphocytes in an allogeneic mixed lymphocyte culture (MLC)using FasL-DC followed by transfer of residual allogeneic T cells in a C57BL/6 toBALB/c GVHD model system (H-2b H-2d). We report here that proliferat...