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

Authors: Schmaltz, C.; Alpdogan, O.; Horndasch, K. J.; Muriglan, S. J.; Kappel, B. J.; Teshima, T.; Ferrara, J. L. M.; Burakoff, S. J.; van den Brink, M. R. M.
Article Title: 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 → 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. © 2001 by The American Society of Hematology.
Keywords: transplantation, homologous; nonhuman; flow cytometry; cd8 antigen; lymphocyte proliferation; t lymphocyte; t-lymphocytes; animal cell; mouse; animals; mice; apoptosis; fas ligand; allogenic bone marrow transplantation; cytotoxicity; enzyme linked immunosorbent assay; cytokine; recombinant tumor necrosis factor; membrane glycoproteins; leukemia cell; graft versus host reaction; perforin; cytotoxicity, immunologic; fas ligand protein; cd4 antigen; bone marrow transplantation; graft vs host disease; graft versus leukemia effect; spleen cell; transplantation immunology; graft vs leukemia effect; pore forming cytotoxic proteins; chromium 51; female; priority journal; article
Journal Title: Blood
Volume: 97
Issue: 9
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 2001-05-01
Start Page: 2886
End Page: 2895
Language: English
DOI: 10.1182/blood.V97.9.2886
PUBMED: 11313285
PROVIDER: scopus
Notes: Export Date: 21 May 2015 -- Source: Scopus
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MSK Authors
  1. Barry J Kappel
    28 Kappel