title: Controlled analysis of nanoparticle charge on mucosal and systemic antibody responses following pulmonary immunization.
abstract: Pulmonary immunization enhances local humoral and cell-mediated mucosal protection, which are critical for vaccination against lung-specific pathogens such as influenza or tuberculosis. A variety of nanoparticle (NP) formulations have been tested preclinically for pulmonary vaccine development, yet the role of NP surface charge on downstream immune responses remains poorly understood. We used the Particle Replication in Non-Wetting Templates (PRINT) process to synthesize hydrogel NPs that varied only in surface charge and otherwise maintained constant size, shape, and antigen loading. Pulmonary immunization with ovalbumin (OVA)-conjugated cationic NPs led to enhanced systemic and lung antibody titers compared with anionic NPs. Increased antibody production correlated with robust germinal center B-cell expansion and increased activated CD4(+) T-cell populations in lung draining lymph nodes. Ex vivo treatment of dendritic cells (DCs) with OVA-conjugated cationic NPs induced robust antigen-specific T-cell proliferation with ∼ 100-fold more potency than soluble OVA alone. Enhanced T-cell expansion correlated with increased expression of surface MHCII, T-cell coactivating receptors, and key cytokines/chemokine expression by DCs treated with cationic NPs, which were not observed with anionic NPs or soluble OVA. Together, these studies highlight the importance of NP surface charge when designing pulmonary vaccines, and our findings support the notion that cationic NP platforms engender potent humoral and mucosal immune responses.
authors.affiliation: Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, NC 27695; and.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Fromen
authors.affiliation: Lineberger Comprehensive Cancer Center, Departments of Microbiology-Immunology and.
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Robbins
authors.affiliation: Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
authors.forename: Tammy W
authors.initials: TW
authors.lastname: Shen
authors.affiliation: Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, NC 27695; and.
authors.forename: Marc P
authors.initials: MP
authors.lastname: Kai
authors.affiliation: Lineberger Comprehensive Cancer Center, Departments of Microbiology-Immunology and desimone@unc.edu jenny_ting@med.unc.edu.
authors.forename: Jenny P Y
authors.initials: JP
authors.lastname: Ting
authors.affiliation: Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, NC 27695; and Lineberger Comprehensive Cancer Center, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 Chemistry, and desimone@unc.edu jenny_ting@med.unc.edu.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: DeSimone
mesh_terms: D000818:Animals; D000917:Antibody Formation; D000941:Antigens / Q000008:administration & dosage; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018925:Chemokines / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology; D020100:Hydrogels / Q000008:administration & dosage / Q000737:chemistry; D018928:Immunity, Mucosal; D007114:Immunization / Q000379:methods*; D008024:Ligands; D008168:Lung / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry*; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D055672:Static Electricity; D013499:Surface Properties; D051193:Toll-Like Receptors / Q000378:metabolism; D022223:Vaccines, Subunit / Q000008:administration & dosage
chemical_list: D000941:Antigens; D018925:Chemokines; D016207:Cytokines; D020100:Hydrogels; D008024:Ligands; D051193:Toll-Like Receptors; D022223:Vaccines, Subunit; D010047:Ovalbumin
keywords: cationic; mucosal; nanoparticle; pulmonary; vaccine