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: 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
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 115 Issue 11 Pg. 3093-103 (Nov 2005) ISSN: 0021-9738 [Print] United States
• PMID: 16224535 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Colony-Stimulating Factors
• Galactosylceramides
• Membrane Proteins
• Recombinant Proteins
• alpha-galactosylceramide
• flt3 ligand protein
• progenipoietin-1
• Granulocyte Colony-Stimulating Factor

Topics

• Animals
• CD4-Positive T-Lymphocytes (physiology)
• CD8-Positive T-Lymphocytes (immunology)
• Colony-Stimulating Factors (pharmacology)
• Dendritic Cells (immunology)
• Female
• Galactosylceramides (physiology)
• Graft vs Leukemia Effect (drug effects, immunology)
• Granulocyte Colony-Stimulating Factor (pharmacology)
• Hematopoietic Stem Cell Mobilization (methods)
• Killer Cells, Natural (drug effects, metabolism)
• Leukemia, Experimental (drug therapy, immunology)
• Membrane Proteins (physiology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Recombinant Proteins (pharmacology)
• Signal Transduction (immunology)
• Stem Cell Transplantation
• T-Lymphocytes (drug effects, metabolism)