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

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 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 7

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The enhanced cytotoxicity observed following donor pretreatment with Pro...
The enhanced cytotoxicity observed following donor pretreatment with ProGP-1 is mediated solely via the perforin pathway. (A) Irradiated B6D2F1 mice received whole spleen from WT, Perforin–/–, TNFα–/–, TRAIL–/–, or FasL–/– donors mobilized with G-CSF or ProGP-1. In vivo cytotoxicity index was determined at day 12 (n = 4 per group). *P < 0.05 ProGP-1 vs. G-CSF within matched donor groups. (B) CD8+ T cells were sort-purified at day 13 from recipients of WT or Perforin–/– spleen and utilized as effectors in 51Cr-release CTL assays; P815 target population. *P < 0.05 WT ProGP-1 vs. all other groups. (C) Total CD8+ T cells per spleen at day 13 after transplant (n = 4 per group). (D) CD8+ T cells were sort-purified at day 13 from recipients of Perforin–/– spleen and utilized as effectors in fluorolysis CTL assays as described in Methods. Host-type target, P815; donor-type target, EL4.