Differential use of Fas ligand and perforin cytotoxic pathways by donor T cells in graft-versus-host disease and graft-versus-leukemia effect

Abstract

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: ...

Functional impairment of human T-lymphocytes following PHA-induced expansion and retroviral transduction: implications for gene therapy

“…23,36 In the hemopoietic stem cell transplant setting, a perforindependent pathway is required for T cell-mediated graftversus-leukemia effect 37 and for T cell-dependent control of EBV-associated post-transplant lymphoproliferative disease. 38 These in vivo findings would further suggest that the functional phenotype that we have just described for iCD3/iCD28-expanded T cells may be advantageous, compared with that of PHA, for adoptive transfer into patients.…”

Interleukin-15 administration increases graft-versus-tumor activity in recipients of haploidentical hematopoietic SCT

“…Previous studies using a similar model system (B6 to B6D2) used a T-cell dose of 20-40 times greater to induce GVT, as well as severe GVHD. 28 Our highest dose of T cells in combination with IL-15 induced only a mild chronic GVHD in a small minority of the recipients (Figure 2e and data not shown). Thus, we suggest the possibility to achieve an enhanced immune reconstitution in HI-HSCT conditions using a small dose of mature donor T cells, and homeostatically expanding the CD8 þ T-cell compartment with IL-15.…”

In vitro-established alloantigen-specific CD8+ CTLs mediate graft-versus-tumor activity in the absence of graft-versus-host disease

“…While TNF-a and perforin are indispensable for anti-tumor activity, CD95L, TNF-a and perforin are responsible for GVHD induction. [21][22][23] The role of TNF-related apoptosis-inducing ligand for the GVT effect is controversially discussed. 4,24 Despite their allogeneic cytotoxicity and expression of death ligands and cytotoxic molecules, transplantation of CTLs did not cause any signs of GVHD in two different BMT models.…”