Abstract
We reported previously that intranasal instillation of a synthetic human pulmonary surfactant with a carboxy vinyl polymer as a viscosity improver, named SF-10, shows potent adjuvanticity for humoral immunity in mice and cynomolgus monkeys. SF-10 effectively induces influenza hemagglutinin vaccine (HAv)-specific IgA in nasal and lung washes and IgG in sera with their neutralizing activities. Since CD8+ T cell-mediated protection is an important requirement for adaptive immunity, we investigated in this study the effects of SF-10 with antigen on local and systemic cell-mediated immunity. Nasal instillation of ovalbumin, a model antigen, combined with SF-10 efficiently delivered antigen to mucosal dendritic and epithelial cells and promoted cross-presentation in antigen presenting cells, yielding a high percentage of ovalbumin-specific cytotoxic T lymphocytes in the nasal mucosa, compared with ovalbumin alone. Nasal immunization of HAv-SF-10 also induced HAv-specific cytotoxic T lymphocytes and upregulated granzyme B expression in splenic CD8+ T cells with their high cytotoxicity against target cells pulsed with HA peptide. Furthermore, nasal vaccination of HAv-SF-10 significantly induced higher cytotoxic T lymphocytes-mediated cytotoxicity in the lungs and cervical lymph nodes in the early phase of influenza virus infection compared with HAv alone. Protective immunity induced by HAv-SF-10 against lethal influenza virus infection was partially and predominantly suppressed after depletion of CD8+ and CD4+ T cells (induced by intraperitoneal injection of the corresponding antibodies), respectively, suggesting that CD4+ T cells predominantly and CD8+ T cells partially contribute to the protective immunity in the advanced stage of influenza virus infection. These results suggest that SF-10 promotes effective antigen delivery to antigen presenting cells, activates CD8+ T cells via cross-presentation, and induces cell-mediated immune responses against antigen.
Highlights
Seasonal influenza A virus (IAV) infection is a major cause of morbidity and mortality, estimated to be responsible for 3–5 million cases of severe illness and ~259,000–500,000 deaths worldwide per annum [1]
The mean fluorescent intensities (MFI) were significantly higher (~3-fold) in OVA-SF-10-treated CD11c+ and CD326+ cells than those treated with OVA alone (P < 0.05)
We investigated the induction of OVA-specific cytotoxic T lymphocytes (CTL), H-2Kb OVA tetramer+ cells in CD8+ T lymphocytes in the nasal mucosa after three courses of intranasal immunization with OVA-SF-10, OVA, or saline and OVA-polyI:C as a positive control [20], in C57BL/6 mice
Summary
Seasonal influenza A virus (IAV) infection is a major cause of morbidity and mortality, estimated to be responsible for 3–5 million cases of severe illness and ~259,000–500,000 deaths worldwide per annum [1]. The currently available influenza vaccines administered intramuscularly or subcutaneously induce a predominantly IgG-mediated protection in the systemic immune compartment and significantly reduce hospitalization and deaths when they match antigenically the circulating viral strains [2]. These vaccinations neither results in adequate induction of antiviral secretory IgA (SIgA), which provides a wide cross-protection, nor efficient prevention of infection at the airway mucosa [2,3,4], or cell-mediated responses with cross-protection in the early phase of infection in the respiratory tract [4,5,6]. For the development of efficient influenza vaccine, CTL induction with a heterosubtypic immunity is strongly desired in addition to the humoral immunity
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