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Blood, 1 January 2001, Vol. 97, No. 1, pp. 114-121
GENE THERAPY
Lentivirus-transduced human monocyte-derived dendritic cells
efficiently stimulate antigen-specific cytotoxic T lymphocytes
Julie Dyall,
Jean-Baptiste Latouche,
Stefan Schnell, and
Michel Sadelain
From the Department of Human Genetics, the Gene
Transfer and Somatic Cell Engineering Facility and the Immunology
Program, Memorial Sloan-Kettering Cancer Center, New York, NY.
Dendritic cells (DCs) are professional antigen-presenting
cells that are highly effective adjuvants for immunizing against pathogens and tumor antigens. The potential merit of genetic approaches to loading DCs with antigens is to express high and sustained levels of
proteins that can be subsequently processed and presented to T
lymphocytes. Replication-defective oncoretroviruses are able to
efficiently transduce CD34+ progenitor-derived DCs but not
monocyte-derived DCs. Here, it is shown that efficient gene transfer is
obtained using a human immunodeficiency virus-1-derived lentiviral
vector deleted of all structural and accessory genes. Infection of
immature DCs with the lentiviral vector at a multiplicity of infection
of 20 resulted in stable gene expression in 30% to 40% of the matured DCs. Proviral DNA was detectable by Alu polymerase chain reaction for
the lentiviral but not the oncoretroviral vector. Most importantly, it
is demonstrated that lentivirus-transduced DCs were fully functional and effectively activated autologous HLA A2.1+ peripheral
blood cytotoxic T lymphocytes (CTLs). DCs expressing lentiviral
vector-encoded Flu peptide were at least as efficient as DCs pulsed
with the same peptide in stimulating specific CTLs. The efficacy of the
lentivirus-transduced DCs was further demonstrated by their ability to
directly activate freshly harvested peripheral blood Flu-specific CTLs
in the absence of CD4+ T-cell help and exogenous cytokines.
The availability of a stable gene delivery system based on a multiply
attenuated lentivirus that does not encode any viral protein and that
allows sustained antigen presentation by DCs derived from blood
monocytes will be very useful for the biologic investigation of DCs and
the improvement of immunotherapeutic strategies involving DCs.
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