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Blood, 1 July 2001, Vol. 98, No. 1, pp. 49-56
GENE THERAPY
Highly efficient gene delivery by mRNA
electroporation in human hematopoietic cells: superiority to
lipofection and passive pulsing of mRNA and to
electroporation of plasmid cDNA for tumor antigen
loading of dendritic cells
Viggo F. I. Van Tendeloo,
Peter Ponsaerts,
Filip Lardon,
Griet Nijs,
Marc Lenjou,
Christine Van
Broeckhoven,
Dirk R. Van
Bockstaele, and
Zwi N. Berneman
From the Laboratory of Experimental Hematology, Antwerp
University Hospital, University of Antwerp; the Laboratory of Molecular
Genetics, Department of Molecular Genetics, Flanders Interuniversity
Institute for Biotechnology (VIB), University of Antwerp; and the
Laboratory of Cancer Research and Clinical Oncology, University of
Antwerp, Antwerp, Belgium.
Designing effective strategies to load human dendritic cells (DCs)
with tumor antigens is a challenging approach for DC-based tumor
vaccines. Here, a cytoplasmic expression system based on mRNA
electroporation to efficiently introduce tumor antigens into DCs is
described. Preliminary experiments in K562 cells using an
enhanced green fluorescent protein (EGFP) reporter gene revealed that
mRNA electroporation as compared with plasmid DNA electroporation showed a markedly improved transfection efficiency (89% versus 40%
EGFP+ cells, respectively) and induced a strikingly lower
cell toxicity (15% death rate with mRNA versus 51% with plasmid DNA).
Next, mRNA electroporation was applied for nonviral transfection
of different types of human DCs, including monocyte-derived DCs
(Mo-DCs), CD34+ progenitor-derived DCs (34-DCs) and
Langerhans cells (34-LCs). High-level transgene expression by mRNA
electroporation was obtained in more than 50% of all DC types.
mRNA-electroporated DCs retained their phenotype and maturational
potential. Importantly, DCs electroporated with mRNA-encoding Melan-A
strongly activated a Melan-A-specific cytotoxic T lymphocyte (CTL)
clone in an HLA-restricted manner and were superior to mRNA-lipofected
or -pulsed DCs. Optimal stimulation of the CTL occurred when Mo-DCs
underwent maturation following mRNA transfection. Strikingly, a
nonspecific stimulation of CTL was observed when DCs were transfected
with plasmid DNA. The data clearly demonstrate that Mo-DCs
electroporated with mRNA efficiently present functional antigenic
peptides to cytotoxic T cells. Therefore, electroporation of
mRNA-encoding tumor antigens is a powerful technique to charge human
dendritic cells with tumor antigens and could serve applications in
future DC-based tumor vaccines.
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