Acetalated Dextran Microparticles for Codelivery of STING and TLR7/8 Agonists
| Autor: | Jenny P.-Y. Ting, Gregory D. Sempowski, Brandon M. Johnson, Robert D. Junkins, Kristy M. Ainslie, Monica M. Johnson, Eric M. Bachelder, Matthew D. Gallovic, Andrew N. Macintyre, Michael A. Collier |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Agonist Male medicine.drug_class Drug Compounding Primary Cell Culture Pharmaceutical Science Article 03 medical and health sciences Mice Immune system Immunogenicity Vaccine Adjuvants Immunologic Drug Discovery medicine Animals Cells Cultured Drug Carriers Immunity Cellular Chemistry Immunogenicity Pathogen-Associated Molecular Pattern Molecules Pattern recognition receptor Imidazoles Biological activity Acetylation Dextrans TLR7 Dendritic Cells Mice Inbred C57BL Sting 030104 developmental biology Toll-Like Receptor 7 Toll-Like Receptor 8 Stimulator of interferon genes Receptors Pattern Recognition Immunology Models Animal Vaccines Subunit Molecular Medicine Female Nucleotides Cyclic |
| Popis: | Vaccines are the most effective tool for preventing infectious diseases; however, subunit vaccines, considered the safest type, suffer from poor immunogenicity and require adjuvants to create a strong and sustained immune response. As adjuvants, pathogen-associated molecular patterns (PAMPs) offer potent immunostimulatory properties and defined mechanisms of action through their cognate pattern recognition receptors (PRRs). Their activity can be further enhanced through combining two or more PAMPs, particularly those that activate multiple immune signaling pathways. However, the cytosolic localization of many PRRs requires intracellular delivery of PAMPs for optimal biological activity, which is particularly true of the stimulator of interferon genes (STING) PRR. Using acetalated dextran (Ace-DEX) microparticles (MPs) encapsulating STING agonist 3'3'-cyclic GMP-AMP (cGAMP) combined with soluble PAMPS, we screened the effect of codelivery of adjuvants using primary mouse bone marrow derived dendritic cells (BMDCs). We identified that codelivery of cGAMP MPs and soluble Toll-like receptor 7/8 (TLR7/8) agonist resiquimod (R848) elicited the broadest cytokine response. cGAMP and R848 were then coencapsulated within Ace-DEX MPs via electrospray. Using the model antigen ovalbumin, we observed that Ace-DEX MPs coencapsulating cGAMP and R848 (cGAMP/R848 Ace-DEX MPs) induced antigen-specific cellular immunity, and a balanced Th1/Th2 humoral response that was greater than cGAMP Ace-DEX MPs alone and PAMPs delivered in separate MPs. These data indicate that polymeric Ace-DEX MPs loaded with STING and TLR7/8 agonists represent a potent cellular and humoral vaccine adjuvant. |
| Databáze: | OpenAIRE |
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