title: Granulocyte colony-stimulating factor-mobilized allogeneic stem cell transplantation maintains graft-versus-leukemia effects through a perforin-dependent pathway while preventing graft-versus-host disease.
abstract: Minimization of graft-versus-host disease (GVHD) with preservation of the graft-versus-leukemia (GVL) effect is a crucial step to improve the overall survival of allogeneic bone marrow transplantation (BMT) for patients with hematological malignancies. We and other investigators have shown that granulocyte colony-stimulating factor (G-CSF)-mobilized allogeneic peripheral stem cell transplantation (PBSCT) reduces the severity of acute GVHD in murine models. In this study, we investigated whether G-CSF-mobilized PBSC maintain their GVL effect in a murine allogeneic transplant model (B6 --> B6D2F1). B6 mice (H-2(b)) were injected subcutaneously with human G-CSF (100 micrograms/kg/d) for 6 days and their splenocytes were harvested on day 7 as a source of PBSC. G-CSF mobilization dramatically improved transplant survival compared with nonmobilized controls (95% v 0%, P <.001). Systemic levels of lipopolysaccharide and tumor necrosis factor-alpha were markedly reduced in recipients of allogeneic G-CSF-mobilized donors, but cytolytic T lymphocyte (CTL) activity against host tumor target cells p815 was retained in those recipients. When leukemia was induced in recipients by coinjection of p815 tumor cells (H-2(d)) at the time of transplantation, all surviving recipients of G-CSF-mobilized B6 donors were leukemia-free at day 70 after transplant, whereas all mice who received T-cell-depleted (TCD) splenocytes from G-CSF-mobilized B6 donors died of leukemia. When splenocytes from G-CSF-mobilized perforin-deficient (pfp-/-) mice were used for transplantation, 90% of recipients died of leukemia, demonstrating that perforin is a crucial pathway mediating GVL effects after G-CSF-mobilized PBSCT. These data illustrate that G-CSF-mobilized allogeneic PBSCT separate GVL from GVHD by preserving perforin-dependent donor CTL activity while reducing systemic inflammation.
authors.affiliation: Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, MA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Pan
authors.forename: T
authors.initials: T
authors.lastname: Teshima
authors.forename: G R
authors.initials: GR
authors.lastname: Hill
authors.forename: D
authors.initials: D
authors.lastname: Bungard
authors.forename: Y S
authors.initials: YS
authors.lastname: Brinson
authors.forename: V S
authors.initials: VS
authors.lastname: Reddy
authors.forename: K R
authors.initials: KR
authors.lastname: Cooke
authors.forename: J L
authors.initials: JL
authors.lastname: Ferrara
mesh_terms: D000818:Animals; D016207:Cytokines / Q000097:blood; D005260:Female; D006086:Graft vs Host Disease / Q000517:prevention & control; D020350:Graft vs Tumor Effect; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology* / Q000627:therapeutic use; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007167:Immunotherapy; D007942:Leukemia, Experimental / Q000276:immunology / Q000628:therapy; D008070:Lipopolysaccharides / Q000097:blood; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D011994:Recombinant Proteins; D013154:Spleen / Q000166:cytology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014184:Transplantation, Homologous; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D054353:Perforin; D016179:Granulocyte Colony-Stimulating Factor