NKT cell-dependent leukemia eradication following stem cell mobilization with potent G-CSF analogs

Edward S. Morris, Kelli P A MacDonald, Vanessa Rowe, Tatjana Banovic, Rachel D. Kuns, Alistair L J Don, Helen M. Bofinger, Angela C. Burman, Stuart D. Olver, Norbert Kienzle, Steven A. Porcelli, Daniel G. Pellicci, Dale I. Godfrey, Mark J. Smyth, Geoffrey R. Hill

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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-SL) chimeric cytokine, progenipoietin-1, markedly expands the splenic and hepatic NKT cell population and enhances functional responses to α-galactosylcerainide. 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.

Original languageEnglish (US)
Pages (from-to)3093-3103
Number of pages11
JournalJournal of Clinical Investigation
Volume115
Issue number11
DOIs
StatePublished - Nov 2005

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Hematopoietic Stem Cell Mobilization
Natural Killer T-Cells
Granulocyte Colony-Stimulating Factor
Leukemia
Transplants
Stem Cell Transplantation
Graft vs Host Disease
Granulocyte Colony-Stimulating Factor Receptors
Immunologic Monitoring
Perforin
Cell- and Tissue-Based Therapy
Protein-Tyrosine Kinases
Hepatocytes
Cytokines
Ligands
T-Lymphocytes
Antigens
Mortality
Population

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Morris, E. S., MacDonald, K. P. A., Rowe, V., Banovic, T., Kuns, R. D., Don, A. L. J., ... Hill, G. R. (2005). NKT cell-dependent leukemia eradication following stem cell mobilization with potent G-CSF analogs. Journal of Clinical Investigation, 115(11), 3093-3103. https://doi.org/10.1172/JCI25249

NKT cell-dependent leukemia eradication following stem cell mobilization with potent G-CSF analogs. / Morris, Edward S.; MacDonald, Kelli P A; Rowe, Vanessa; Banovic, Tatjana; Kuns, Rachel D.; Don, Alistair L J; Bofinger, Helen M.; Burman, Angela C.; Olver, Stuart D.; Kienzle, Norbert; Porcelli, Steven A.; Pellicci, Daniel G.; Godfrey, Dale I.; Smyth, Mark J.; Hill, Geoffrey R.

In: Journal of Clinical Investigation, Vol. 115, No. 11, 11.2005, p. 3093-3103.

Research output: Contribution to journalArticle

Morris, ES, MacDonald, KPA, Rowe, V, Banovic, T, Kuns, RD, Don, ALJ, Bofinger, HM, Burman, AC, Olver, SD, Kienzle, N, Porcelli, SA, Pellicci, DG, Godfrey, DI, Smyth, MJ & Hill, GR 2005, 'NKT cell-dependent leukemia eradication following stem cell mobilization with potent G-CSF analogs', Journal of Clinical Investigation, vol. 115, no. 11, pp. 3093-3103. https://doi.org/10.1172/JCI25249
Morris, Edward S. ; MacDonald, Kelli P A ; Rowe, Vanessa ; Banovic, Tatjana ; Kuns, Rachel D. ; Don, Alistair L J ; Bofinger, Helen M. ; Burman, Angela C. ; Olver, Stuart D. ; Kienzle, Norbert ; Porcelli, Steven A. ; Pellicci, Daniel G. ; Godfrey, Dale I. ; Smyth, Mark J. ; Hill, Geoffrey R. / NKT cell-dependent leukemia eradication following stem cell mobilization with potent G-CSF analogs. In: Journal of Clinical Investigation. 2005 ; Vol. 115, No. 11. pp. 3093-3103.
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