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NKT cell–dependent leukemia eradication following stem cell mobilization with potent G-CSF analogs
Edward S. Morris, … , Mark J. Smyth, Geoffrey R. Hill
Edward S. Morris, … , Mark J. Smyth, Geoffrey R. Hill
Published November 1, 2005
Citation Information: J Clin Invest. 2005;115(11):3093-3103. https://doi.org/10.1172/JCI25249.
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Research Article Oncology Article has an altmetric score of 12

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

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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-3L) chimeric cytokine, progenipoietin-1, markedly expands the splenic and hepatic NKT cell population and enhances functional responses to α-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

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Figure 2

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ProGP-1 enhances CD8+ T cell cytotoxicity following allogeneic SCT. (A) ...
ProGP-1 enhances CD8+ T cell cytotoxicity following allogeneic SCT. (A) Irradiated B6D2F1 mice received whole spleen from donors mobilized with G-CSF or ProGP-1. In vivo cytotoxicity was determined as described in Methods (syngeneic, n = 3 per group; allogeneic, n = 5 per group). *P = 0.008 G-CSF allogeneic vs. ProGP-1 allogeneic. (B) At day 13 after SCT, whole spleen was utilized as the effector population in 51Cr-release CTL assays; host-type target, P815; donor-type target, EL4. **P < 0.05 vs. other groups. One of 2 identical experiments shown. (C) Irradiated B6D2F1 mice received whole spleen, CD4+- or CD8β+-depleted spleen, or CD4+- and CD8β+-depleted spleen from WT donors (n = 9 per group). Additional cohorts received whole spleen from Jα18–/– donors or CD4+-depleted spleen from WT donors supplemented with purified CD4+ T cells from WT or Jα18–/– donors (n = 5 per group). All donors were mobilized with ProGP-1. In vivo cytotoxicity was determined at day 12. **P < 0.05 vs. WT whole spleen. Combined data from 2 experiments shown. (D) CD8+ T cells were sort-purified at day 13 from recipients of whole WT spleen, CD4+-depleted spleen, or whole Jα18–/– spleen and utilized as effectors in 51Cr-release CTL assays. **P < 0.05 WT nondepleted anti-host vs. WT CD4+-depleted anti-host or Jα18–/– anti-host. (E) Irradiated B6D2F1 mice received grafts from WT or Jα18–/– donors mobilized with G-CSF or ProGP-1; in vivo cytotoxicity index was determined at day 12 (n = 6 per group). #P = 0.002 WT ProGP-1 vs. Jα18–/– ProGP-1. (F) CD8+ T cells were sort-purified at day 13 and utilized as effectors in 51Cr-release CTL assays; P815 target population. **P < 0.05 WT ProGP-1 vs. all other groups.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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