Synergistic antileukemia effect of combinational gene therapy using murine beta-defensin 2 and IL-18 in L1210 murine leukemia model.
Murine beta-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-1beta 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-gamma 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.
Xu
B
B
State Key Laboratory for Experimental Hematology, Institute of Hematology, Chinese Academy of Medical Sciences, Peking Union Medical College, Tianjin, China.
Dong
C-Y
CY
Zhang
F
F
Lin
Y-M
YM
Wu
K-F
KF
Ma
X-T
XT
D000818:Animals; D001681:Biological Assay / Q000379:methods; D019496:Cancer Vaccines / Q000235:genetics / Q000627:therapeutic use*; D002460:Cell Line; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics; D007371:Interferon-gamma / Q000276:immunology; D020382:Interleukin-18 / Q000235:genetics*; D053583:Interleukin-1beta / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology; D007945:Leukemia, Lymphoid / Q000276:immunology / Q000628:therapy*; D008213:Lymphocyte Activation; D051379:Mice; D023421:Models, Animal; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014162:Transfection / Q000379:methods; D019076:Transgenes; D023083:beta-Defensins / Q000235:genetics*
D019496:Cancer Vaccines; C106641:DEFB4A protein, human; D020382:Interleukin-18; D053583:Interleukin-1beta; D023083:beta-Defensins; D007371:Interferon-gamma