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Synergistic antileukemia effect of combinational gene therapy using murine b-defensin 2 and IL-18 in L1210 murine leukemia model

Abstract

Murine β-defensin 2 (MBD2) is not only chemotactic for immature dendritic cells but also activates them by Toll-like receptor 4. We have previously demonstrated that vaccine with MBD2 elicited potent antileukemia responses in the L1210 murine model. Interleukin-18 (IL-18) is an essential cytokine for the generation of Th1 response and natural killer cells and cytotoxic T lymphocytes (CTL) activation. As MBD2 and IL-18 appear to function on different components required by an effective antitumor immune response including both innate and adaptive immunity, we investigated whether combinatorial delivery of MBD2 and IL-18 transduced L1210 cells could elicit synergistic antileukemia effects. First, we constructed a single plasmid vector carrying both pro-IL-18 and IL-1β converting enzyme (ICE) genes, and found that transfection of this vector into L1210 cells resulted in efficient secretion of bioactive IL-18. Combinatorial delivery of MBD2 and pro-IL-18-ICE modified L1210 cells conferred a superior inhibition of leukemogenicity over either L1210-MBD2 or L1210-pro-IL-18-ICE alone; moreover, the survived mice developed long-lasting protective immunity as determined by rechallenge experiments. This combined vaccine also elicited the most marked therapeutic effect, CTL activity and interferon-γ production. These results suggest that the combination of MBD2 and IL-18 induces more effective antileukemia activity and provides a promising strategy for cancer therapy.

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Acknowledgements

This study was supported by National Natural Science Foundation of China 30471964, and Natural Science Foundation of Tianjin 05YFJMJC 02200.

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Correspondence to X-T Ma.

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Xu, B., Dong, CY., Zhang, F. et al. Synergistic antileukemia effect of combinational gene therapy using murine b-defensin 2 and IL-18 in L1210 murine leukemia model. Gene Ther 14, 1181–1187 (2007). https://doi.org/10.1038/sj.gt.3302966

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