title: NKT cell-dependent leukemia eradication following stem cell mobilization with potent G-CSF analogs.
abstract: NKT cells have pivotal roles in immune regulation and tumor immunosurveillance. We report that the G-CSF and FMS-like tyrosine kinase 3 ligand (Flt-3L) chimeric cytokine, progenipoietin-1, markedly expands the splenic and hepatic NKT cell population and enhances functional responses to alpha-galactosylceramide. In a murine model of allogeneic stem cell transplantation, donor NKT cells promoted host DC activation and enhanced perforin-restricted CD8+ T cell cytotoxicity against host-type antigens. Following leukemic challenge, donor treatment with progenipoietin-1 significantly improved overall survival when compared with G-CSF or control, attributable to reduced graft-versus-host disease mortality and paradoxical augmentation of graft-versus-leukemia (GVL) effects. Enhanced cellular cytotoxicity was dependent on donor NKT cells, and leukemia clearance was profoundly impaired in recipients of NKT cell-deficient grafts. Enhanced cytotoxicity and GVL effects were not associated with Flt-3L signaling or effects on DCs but were reproduced by prolonged G-CSF receptor engagement with pegylated G-CSF. Thus, modified G-CSF signaling during stem cell mobilization augments NKT cell-dependent CD8+ cytotoxicity, effectively separating graft-versus-host disease and GVL and greatly expanding the potential applicability of allogeneic stem cell transplantation for the therapy of malignant disease.
authors.affiliation: Queensland Institute of Medical Research, Brisbane, Queensland, Australia.
authors.forename: Edward S
authors.initials: ES
authors.lastname: Morris
authors.forename: Kelli P A
authors.initials: KP
authors.lastname: MacDonald
authors.forename: Vanessa
authors.initials: V
authors.lastname: Rowe
authors.forename: Tatjana
authors.initials: T
authors.lastname: Banovic
authors.forename: Rachel D
authors.initials: RD
authors.lastname: Kuns
authors.forename: Alistair L J
authors.initials: AL
authors.lastname: Don
authors.forename: Helen M
authors.initials: HM
authors.lastname: Bofinger
authors.forename: Angela C
authors.initials: AC
authors.lastname: Burman
authors.forename: Stuart D
authors.initials: SD
authors.lastname: Olver
authors.forename: Norbert
authors.initials: N
authors.lastname: Kienzle
authors.forename: Steven A
authors.initials: SA
authors.lastname: Porcelli
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Pellicci
authors.forename: Dale I
authors.initials: DI
authors.lastname: Godfrey
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
authors.forename: Geoffrey R
authors.initials: GR
authors.lastname: Hill
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003115:Colony-Stimulating Factors / Q000494:pharmacology; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D005699:Galactosylceramides / Q000502:physiology; D020544:Graft vs Leukemia Effect / Q000187:drug effects / Q000276:immunology; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods*; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000378:metabolism; D007942:Leukemia, Experimental / Q000188:drug therapy* / Q000276:immunology; D008565:Membrane Proteins / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000276:immunology; D033581:Stem Cell Transplantation; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism
chemical_list: D003115:Colony-Stimulating Factors; D005699:Galactosylceramides; D008565:Membrane Proteins; D011994:Recombinant Proteins; C493154:alpha-galactosylceramide; C084881:flt3 ligand protein; C434603:progenipoietin-1; D016179:Granulocyte Colony-Stimulating Factor