In allogeneic bone marrow transplantation (BMT) donor T cells are primarily responsible for antihost activity, resulting in graft-versus-host disease (GVHD), and for antileukemia activity, resulting in the graft-versus-leukemia (GVL) effect. The relative contributions of the Fas ligand (FasL) and perforin cytotoxic pathways in GVHD and GVL activity were studied by using FasL-defective or perforin-deficient donor T cells in murine parent 3 F1 models for allogeneic bone marrow transplantation. It was found that FasL-defective B6.gld donor T cells display diminished GVHD activity but have intact GVL activity. In contrast, perforin-deficient B6.pfp ؊/؊ donor T cells have intact GVHD activity but display diminished GVL activity. Splenic T cells from recipients of B6.gld or B6.pfp ؊/؊ T cells had identical proliferative and cytokine responses to host antigens; however, splenic T cells from recipients of B6.pfp ؊/؊ T cells had no cytolytic activity against leukemia cells in a cytotoxicity assay. In experiments with selected CD4 ؉ or CD8 ؉ donor T cells, the FasL pathway was important for GVHD activity by both CD4 ؉ and CD8 ؉ T cells, whereas the perforin pathway was required for CD8-mediated GVL activity.These data demonstrate in a murine model for allogeneic bone marrow transplantation that donor T cells mediate GVHD activity primarily through the FasL effector pathway and GVL activity through the perforin pathway. This suggests that donor T cells make differential use of cytolytic pathways and that the specific blockade of one cytotoxic pathway may be used to prevent GVHD without interfering with GVL activity. IntroductionAllogeneic bone marrow transplantation (BMT) is an important therapeutic modality for a variety of diseases, including hematologic malignancies. The therapeutic benefits of allogeneic BMT are not only derived from the high dose of chemoradiation but also from a graft-versus-leukemia (GVL) effect. [1][2][3] Clinical evidence for a GVL effect comes from studies demonstrating an increased relapse rate after BMT from an identical twin, autologous BMT, and T-cell depletion of the allogeneic bone marrow (BM) graft (reviewed in Truitt and Johnson 3 and Antin 4 ). Most studies indicate that the GVL effect is primarily mediated by allogeneic donor T cells, which recognize either leukemia-specific antigens or alloantigens expressed on normal and malignant cells. [5][6][7][8] Graft-versus-host disease (GVHD) remains the single most important complication of allogeneic BMT and is defined as a progressive systemic illness with immunosuppression, cachexia, and specific target organ disease of the skin, liver, and intestines. 9 Although the complex pathophysiology of acute GVHD involves the conditioning regimen (radiation or chemotherapy), cytokines, nitric oxide, and non-T effector cells (reviewed in Krenger et al 10 ), the cytolytic activity of donor T cells is essential for the development of GVHD activity.Cytolytic activity of cytotoxic T lymphocytes (CTL) is primarily mediated through 2 effector mechanisms: ...

The Fas/Fas ligand (FasL) pathway is involved in a variety of regulatory mechanisms that could be important for the development of graft-vs-host disease (GVHD) after bone marrow transplantation (BMT), such as cytolysis of target cells by cytotoxic T cells, regulation of inflammatory responses, peripheral deletion of autoimmune cells, costimulation of T cells, and activation-induced cell death. To further evaluate the role of Fas/FasL in the complex pathophysiology of GVHD, we used Fas-deficient B6.lpr mice as recipients in a MHC-matched minor histocompatibility Ag-mismatched murine model for GVHD after allogeneic BMT (C3H.SW→B6). We found a significantly higher morbidity and mortality from GVHD compared with control B6 recipients. In contrast, B6.lpr recipients had very little hepatic GVHD, although all other specific GVHD target organs (skin, intestines, and thymus) were more severely affected than in the control B6 recipients. B6.lpr recipients with GVHD demonstrated intact donor lymphoid engraftment and an increase in expansion of donor T cells and monocytes/macrophages compared with control B6 recipients. Serum levels of IFN-γ and TNF-α were higher in B6.lpr recipients than in control B6 recipients, and monocytes/macrophages in B6.lpr recipients appeared more sensitized. B6.lpr recipients had more residual peritoneal macrophages after BMT, and peritoneal macrophages from B6.lpr mice could induce a greater proliferative response from C3H.SW splenocytes. This study demonstrates that the expression of Fas in the recipient is required for GVHD of the liver, but shows unexpected consequences when host tissues lack the expression of Fas for the development of GVHD in other organs and systemic GVHD.