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Intradermal Delivery of TLR Agonists in a Human Explant Skin Model: Preferential Activation of Migratory Dendritic Cells by Polyribosinic-Polyribocytidylic Acid and Peptidoglycans

Oosterhoff, Dinja ; Heusinkveld, Moniek ; Lougheed, Sinead M. ; Kosten, Ilona ; Lindstedt, Malin LU ; Bruijns, Sven C. M. ; van Es, Thomas ; van Kooyk, Yvette ; van der Burg, Sjoerd H. and de Gruijl, Tanja D. (2013) In Journal of Immunology 190(7). p.3338-3345
Abstract
TLR agonists are attractive candidate adjuvants for therapeutic cancer vaccines as they can induce a balanced humoral and T cell-mediated immune response. With a dense network of dendritic cells (DCs) and draining lymphatics, the skin provides an ideal portal for vaccine delivery. Beside direct DC activation, TLR agonists may also induce DC activation through triggering the release of inflammatory mediators by accessory cells in the skin microenvironment. Therefore, a human skin explant model was used to explore the in vivo potential of intradermally delivered TLR agonists to stimulate Langerhans cells and dermal DCs in their natural complex tissue environment. The skin-emigrated DCs were phenotyped and analyzed for T cell stimulatory... (More)
TLR agonists are attractive candidate adjuvants for therapeutic cancer vaccines as they can induce a balanced humoral and T cell-mediated immune response. With a dense network of dendritic cells (DCs) and draining lymphatics, the skin provides an ideal portal for vaccine delivery. Beside direct DC activation, TLR agonists may also induce DC activation through triggering the release of inflammatory mediators by accessory cells in the skin microenvironment. Therefore, a human skin explant model was used to explore the in vivo potential of intradermally delivered TLR agonists to stimulate Langerhans cells and dermal DCs in their natural complex tissue environment. The skin-emigrated DCs were phenotyped and analyzed for T cell stimulatory capacity. We report that, of six tested TLR-agonists, the TLR2 and -3 agonists peptidoglycan (PGN) and polyribosinic-polyribocytidylic acid (Poly I:C) were uniquely able to enhance the T cell-priming ability of skin-emigrated DCs, which, in the case of PGN, was accompanied by Th1 polarization. The enhanced priming capacity of Poly I:C-stimulated DCs was associated with a strong upregulation of appropriate costimulatory molecules, including CD70, whereas that of PGN-stimulated DCs was associated with the release of a broad array of proinflammatory cytokines. Transcriptional profiling further supported the notion that the PGN- and Poly I:C-induced effects were mediated through binding to TLR2/nucleotide-binding oligomerization domain 2 and TLR3/MDA5, respectively. These data warrant further exploration of PGN and Poly I:C, alone or in combination, as DC-targeted adjuvants for intradermal cancer vaccines. The Journal of Immunology, 2013, 190:3338-3345. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Immunology
volume
190
issue
7
pages
3338 - 3345
publisher
American Association of Immunologists
external identifiers
  • wos:000316610700035
  • scopus:84875426050
  • pmid:23467931
ISSN
1550-6606
DOI
10.4049/jimmunol.1200598
language
English
LU publication?
yes
id
136f83a7-6eef-4638-99a6-10396a342b94 (old id 3748542)
date added to LUP
2016-04-01 14:23:39
date last changed
2019-11-20 03:03:02
@article{136f83a7-6eef-4638-99a6-10396a342b94,
  abstract     = {TLR agonists are attractive candidate adjuvants for therapeutic cancer vaccines as they can induce a balanced humoral and T cell-mediated immune response. With a dense network of dendritic cells (DCs) and draining lymphatics, the skin provides an ideal portal for vaccine delivery. Beside direct DC activation, TLR agonists may also induce DC activation through triggering the release of inflammatory mediators by accessory cells in the skin microenvironment. Therefore, a human skin explant model was used to explore the in vivo potential of intradermally delivered TLR agonists to stimulate Langerhans cells and dermal DCs in their natural complex tissue environment. The skin-emigrated DCs were phenotyped and analyzed for T cell stimulatory capacity. We report that, of six tested TLR-agonists, the TLR2 and -3 agonists peptidoglycan (PGN) and polyribosinic-polyribocytidylic acid (Poly I:C) were uniquely able to enhance the T cell-priming ability of skin-emigrated DCs, which, in the case of PGN, was accompanied by Th1 polarization. The enhanced priming capacity of Poly I:C-stimulated DCs was associated with a strong upregulation of appropriate costimulatory molecules, including CD70, whereas that of PGN-stimulated DCs was associated with the release of a broad array of proinflammatory cytokines. Transcriptional profiling further supported the notion that the PGN- and Poly I:C-induced effects were mediated through binding to TLR2/nucleotide-binding oligomerization domain 2 and TLR3/MDA5, respectively. These data warrant further exploration of PGN and Poly I:C, alone or in combination, as DC-targeted adjuvants for intradermal cancer vaccines. The Journal of Immunology, 2013, 190:3338-3345.},
  author       = {Oosterhoff, Dinja and Heusinkveld, Moniek and Lougheed, Sinead M. and Kosten, Ilona and Lindstedt, Malin and Bruijns, Sven C. M. and van Es, Thomas and van Kooyk, Yvette and van der Burg, Sjoerd H. and de Gruijl, Tanja D.},
  issn         = {1550-6606},
  language     = {eng},
  number       = {7},
  pages        = {3338--3345},
  publisher    = {American Association of Immunologists},
  series       = {Journal of Immunology},
  title        = {Intradermal Delivery of TLR Agonists in a Human Explant Skin Model: Preferential Activation of Migratory Dendritic Cells by Polyribosinic-Polyribocytidylic Acid and Peptidoglycans},
  url          = {http://dx.doi.org/10.4049/jimmunol.1200598},
  doi          = {10.4049/jimmunol.1200598},
  volume       = {190},
  year         = {2013},
}