Targeted delivery of TLR ligands to human and mouse dendritic cells strongly enhances adjuvanticity

• Published in: Blood Vol. 118; no. 26; pp. 6836 - 6844
• Main Authors: Tacken, Paul J., Zeelenberg, Ingrid S., Cruz, Luis J., van Hout-Kuijer, Maaike A., van de Glind, Gerline, Fokkink, Remco G., Lambeck, Annechien J.A., Figdor, Carl G.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 22.12.2011; Americain Society of Hematology
• Subjects: activation; Adjuvants, Immunologic - administration & dosage; Animals; antigen presentation; Biological and medical sciences; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cells, Cultured; cross-presentation; Cytokines - blood; Cytokines - immunology; Cytokines - metabolism; Cytotoxicity, Immunologic - immunology; Dendritic Cells - immunology; Dendritic Cells - metabolism; Drug Delivery Systems - methods; Female; Flow Cytometry; Hematologic and hematopoietic diseases; Humans; immunity; in-vivo; Ligands; Lymphocyte Activation - immunology; Male; Medical sciences; Mice; Mice, Inbred C57BL; Microscopy, Confocal; Monocytes - immunology; Monocytes - metabolism; Nanoparticles - administration & dosage; polyribocytidylic acid; receptor; responses; t-cells; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - metabolism; Time Factors; Toll-Like Receptors - immunology; Toll-Like Receptors - metabolism; tumor-necrosis-factor; Vaccines - administration & dosage; Vaccines - immunology; Human; Dendritic cell; Vertebrata; Mammalia; Targeting; Hematology; Mouse; Antigen presenting cell; Ligand; Animal; Rodentia; Toll like receptor
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2011-07-367615

Effective vaccines consist of 2 components: immunodominant antigens and effective adjuvants. Whereas it has been demonstrated that targeted delivery of antigens to dendritic cells (DCs) improves vaccine efficacy, we report here that co-targeting of TLR ligands (TLRLs) to DCs strongly enhances adjuvanticity and immunity. We encapsulated ligands for intracellular TLRs within biodegradable nanoparticles coated with Abs recognizing DC-specific receptors. Targeted delivery of TLRLs to human DCs enhanced the maturation and production of immune stimulatory cytokines and the Ag-specific activation of naive CD8+ T cells. In vivo studies demonstrated that nanoparticles carrying Ag induced cytotoxic T-lymphocyte responses at 100-fold lower adjuvant dose when TLRLs were co-encapsulated instead of administered in soluble form. Moreover, the efficacy of these targeted TLRLs reduced the serum cytokine storm and related toxicity that is associated with administration of soluble TLRLs. We conclude that the targeted delivery of adjuvants may improve the efficacy and safety of DC-based vaccines.