Conditioning of the injection site with CpG enhances the migration of adoptively transferred dendritic cells and endogenous CD8+ T-cell responses.
The efficiency of immunotherapy using tumor-antigen-loaded dendritic cells (DCs) is severely limited by the impaired migration of injected cells from the application site to the draining lymph nodes. As described earlier, pretreatment of the injection site with inflammatory cytokines enhances DC migration. We wanted to test whether toll-like receptor (TLR) ligands can improve migration of murine bone marrow-derived DC (BMDC) and the subsequent T-cell responses. For this purpose, we established an experimental setup closely resembling human vaccination protocols that served to investigate DC migration from the skin to the draining lymph nodes. We observed that BMDC, matured with a cytokine cocktail (tumor necrosis factor-alpha, interleukin-beta, interleukin-6, prostaglandin E2), strongly expressed CCR7. The migration efficiency of adoptively transferred mature BMDCs was determined by the number of cells injected and the application site. We decided to inject DC intradermally into the ear skin and investigated the effects of pretreatment of the injection site with various TLR ligands. Conditioning of the skin site with the TLR ligands CpG and Peptidoglycan increased the number of DCs arriving in the lymph node. Mechanical stress applied to the skin, such as tape stripping of the skin was equally effective. Importantly, only pretreatment with CpG enhanced responses of endogenous CD8 T cells. Thus, conditioning of the injection site with the TLR ligand CpG could be a new promising way to improve the outcome of DC immunotherapy.
Department of Dermatology and Venereology, Innsbruck Medical University, A-6020 Innsbruck, Austria.
Christoph H
CH
Tripp
Susanne
S
Ebner
Gudrun
G
Ratzinger
Nikolaus
N
Romani
Patrizia
P
Stoitzner
D019264:Adoptive Transfer; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism*; D019496:Cancer Vaccines; D002465:Cell Movement / Q000187:drug effects* / Q000276:immunology; D002478:Cells, Cultured; D004247:DNA / Q000494:pharmacology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D007093:Imidazoles / Q000494:pharmacology; D007271:Injections, Intradermal; D008070:Lipopolysaccharides / Q000494:pharmacology; D008198:Lymph Nodes / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009838:Oligodeoxyribonucleotides; D010457:Peptidoglycan / Q000494:pharmacology; D054400:Receptors, CCR7 / Q000276:immunology / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000473:pathology; D051193:Toll-Like Receptors / Q000819:agonists
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; C515371:Ccr7 protein, mouse; C423449:CpG ODN 1826; D007093:Imidazoles; D008070:Lipopolysaccharides; D009838:Oligodeoxyribonucleotides; D010457:Peptidoglycan; D054400:Receptors, CCR7; D051193:Toll-Like Receptors; D004247:DNA; C402365:resiquimod