title: Tuning the immune response of dendritic cells to surface-assembled poly(I:C) on microspheres through synergistic interactions between phagocytic and TLR3 signaling.
abstract: The artificial dsRNA polyriboinosinic acid-polyribocytidylic acid, poly(I:C), is a potent adjuvant candidate for vaccination, as it strongly drives cell-mediated immunity. However, because of its effects on non-immune bystander cells, poly(I:C) administration may bear danger for the development of autoimmune diseases. Thus poly(I:C) should be applied in the lowest dose possible. We investigated microspheres carrying surface-assembled poly(I:C) as a two-in-one adjuvant formulation to stimulate maturation of monocyte-derived dendritic cells (MoDCs). Negatively charged polystyrene microspheres were equipped with a poly(ethylene glycol) corona through electrostatically driven surface assembly of a library of polycationic poly(l-lysine)-graft-poly(ethylene glycol) copolymers, PLL-g-PEG. Stable surface assembly of poly(I:C) was achieved by incubation of polymer-coated microspheres in an aqueous poly(I:C) solution. Surface-assembled poly(I:C) exhibited a strongly enhanced efficacy to stimulate maturation of MoDCs by up to two orders of magnitude, as compared to free poly(I:C). Multiple phagocytosis events were the key factor to enhance the efficacy. The cytokine secretion pattern of MoDCs after exposure to surface-assembled poly(I:C) differed from that of free poly(I:C), while their ability to stimulate T cell proliferation was similar. Overall, phagocytic signaling plays an important role in defining the resulting immune response to such two-in-one adjuvant formulations.
authors.affiliation: Institute of Pharmaceutical Sciences, ETH Zurich, Zurich 8093, Switzerland.
authors.forename: Annina M
authors.initials: AM
authors.lastname: Hafner
authors.forename: Blaise
authors.initials: B
authors.lastname: Corthésy
authors.forename: Marcus
authors.initials: M
authors.lastname: Textor
authors.forename: Hans P
authors.initials: HP
authors.lastname: Merkle
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007109:Immunity / Q000187:drug effects*; D007114:Immunization; D008213:Lymphocyte Activation / Q000187:drug effects; D008863:Microspheres; D009000:Monocytes / Q000166:cytology; D010586:Phagocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D011070:Poly I-C / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000494:pharmacology; D011107:Polylysine / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D013499:Surface Properties / Q000187:drug effects; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D051196:Toll-Like Receptor 3 / Q000378:metabolism*
chemical_list: D016207:Cytokines; D051196:Toll-Like Receptor 3; D011107:Polylysine; D011092:Polyethylene Glycols; D011070:Poly I-C