title: In situ engineering of the lymph node microenvironment via intranodal injection of adjuvant-releasing polymer particles.
abstract: Recent studies have demonstrated a simple, potentially universal strategy to enhance vaccine potency, via intralymph node (i.LN) injection. To date, intranodal immunization studies have focused on the delivery of unadjuvanted vaccines (e.g., naked DNA, peptide, or protein). We hypothesized that combining i.LN vaccination with controlled release biomaterials permitting sustained dosing of molecular adjuvants to the local tissue microenvironment would further enhance this promising vaccination strategy. To test this idea, we encapsulated the Toll-like receptor-3 ligand poly(inosinic:cytidylic acid) (polyIC) in biodegradable poly(lactide-co-glycolide) microparticles (MPs) designed to remain extracellular and release polyIC in the LN over several days. Intranodal injection of MPs increased persistence of polyIC in LNs compared to the same dose of soluble polyIC or polyIC formulated in nanoparticles, leading to increased accumulation of Toll-like receptor agonist in LN-resident antigen presenting cells and more enduring dendritic cell activation. Intralymph node injection of ovalbumin mixed with polyIC-releasing MPs enhanced the humoral response and expanded ovalbumin-specific T cells to frequencies as high as 18% among all CD8(+) cells following a single injection (8.2-fold greater than the same vaccine given i.m.), a response that could not be matched by antigen mixed with polyIC-loaded nanoparticles or a 10-fold greater dose of soluble polyIC. Thus, i.LN immunization with slow release-formulated adjuvants may be a broadly applicable strategy to enhance therapeutic or prophylactic vaccines.
authors: Department of Material Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors: Christopher M
authors: CM
authors: Jewell
authors: Sandra C Bustamante
authors: SC
authors: López
authors: Darrell J
authors: DJ
authors: Irvine
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D060833:Cellular Microenvironment / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D005456:Fluorescent Dyes / Q000737:chemistry; D007114:Immunization / Q000379:methods; D008163:Luminescent Measurements / Q000379:methods; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000737:chemistry*; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D010316:Particle Size; D011070:Poly I-C / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology*; D011098:Polyglactin 910 / Q000737:chemistry; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D005456:Fluorescent Dyes; D011098:Polyglactin 910; D010047:Ovalbumin; D011070:Poly I-C