Maturation of dendritic cells accompanies high-efficiency gene transfer by a CD40-targeted adenoviral vector.
Important therapeutic applications of genetically modified dendritic cells (DC) have been proposed; however, current vector systems have demonstrated only limited gene delivery efficacy to this cell type. By means of bispecific Abs, we have dramatically enhanced gene transfer to monocyte derived DC (MDDC) by retargeting adenoviral (Ad) vectors to a marker expressed on DC, CD40. Adenovirus targeted to CD40 demonstrated dramatic improvements in gene transfer relative to untargeted Ad vectors. Fundamental to the novelty of this system is the capacity of the vector itself to modulate the immunological status of the MDDC. This vector induces DC maturation as demonstrated phenotypically by increased expression of CD83, MHC, and costimulatory molecules, as well as functionally by production of IL-12 and an enhanced allostimulatory capacity in a MLR. In comparing this vector to other Ad-based gene transfer systems, we have illustrated that the features of DC maturation are not a function of the Ad particle, but rather a consequence of targeting to the CD40 marker. This vector approach may thus mediate not only high-efficiency gene delivery but also serve a proactive role in DC activation that could ultimately strengthen the utility of this vector for immunotherapy strategies.
Tillman
B W
BW
Gene Therapy Program, University of Alabama, Birmingham 35294, USA.
de Gruijl
T D
TD
Luykx-de Bakker
S A
SA
Scheper
R J
RJ
Pinedo
H M
HM
Curiel
T J
TJ
Gerritsen
W R
WR
Curiel
D T
DT
D000260:Adenoviruses, Human / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D019013:CD40 Antigens / Q000235:genetics*; D002452:Cell Count; D002454:Cell Differentiation / Q000276:immunology; D002460:Cell Line; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D004306:Dose-Response Relationship, Immunologic; D004770:Enterovirus / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000939:Epitopes / Q000235:genetics; D015967:Gene Expression Regulation, Viral / Q000276:immunology; D005822:Genetic Vectors / Q000276:immunology; D006801:Humans; D016130:Immunophenotyping; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D011991:Receptors, Virus / Q000172:deficiency / Q000235:genetics
D019013:CD40 Antigens; C568771:CLMP protein, human; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D000939:Epitopes; D011991:Receptors, Virus